WO2017113031A1 - Pyrimido-isoquinolin-quinone derivative compounds, and pharmaceutically acceptable salts, isomers and tautomers thereof; pharmaceutical composition; preparation method; and use thereof in the treatment of diseases caused by bacteria and multidrug-resistant bacteria - Google Patents

Pyrimido-isoquinolin-quinone derivative compounds, and pharmaceutically acceptable salts, isomers and tautomers thereof; pharmaceutical composition; preparation method; and use thereof in the treatment of diseases caused by bacteria and multidrug-resistant bacteria Download PDF

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Publication number
WO2017113031A1
WO2017113031A1 PCT/CL2016/050080 CL2016050080W WO2017113031A1 WO 2017113031 A1 WO2017113031 A1 WO 2017113031A1 CL 2016050080 W CL2016050080 W CL 2016050080W WO 2017113031 A1 WO2017113031 A1 WO 2017113031A1
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Prior art keywords
alkyl
isoquinolin
ethyl
tetraone
group
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PCT/CL2016/050080
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Spanish (es)
French (fr)
Inventor
David Reinaldo VÁSQUEZ VELÁSQUEZ
Juan Andrés ANDRADES LAGOS
Javier Andrés CAMPANINI SALINAS
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Universidad De Chile
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Application filed by Universidad De Chile filed Critical Universidad De Chile
Priority to EP16880235.3A priority Critical patent/EP3404026B1/en
Priority to US16/067,033 priority patent/US11390622B2/en
Priority to ES16880235T priority patent/ES2951489T3/en
Priority to MX2018008192A priority patent/MX2018008192A/en
Priority to CN201680081761.1A priority patent/CN109121411B/en
Publication of WO2017113031A1 publication Critical patent/WO2017113031A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to antibacterial compounds derived from a pyrimido-isoquinolinquinone nucleus, processes for its preparation, and methods for its use.
  • cephalosporins were also a breakthrough in antibiotic therapy. Near the mouth of the drain on the Sardinian Coast, the Italian Giuseppe Brotzu of the University of Cagliari isolated the new beta-lactam of "Cephalosporium acremonium", the first source of these drugs.
  • the subsequent discovery of the active nucleus of cephalosporin C and the possibility of adding side chains made it possible to develop new semi-synthetic compounds with a much greater antibacterial activity. Macrolides, effective against Gram positive, an alternative in patients allergic to penicicillin, they started their itinerary with erythromycin; This "effective oral” antibiotic is produced by the "S. Erythreus” strain obtained from the soil of the Philippine archipelago [5]. Subsequently, other types of antibiotics were developed, until reaching the arsenal with which medicine currently has.
  • antibiotic was only used to refer to organic compounds of biological origin, which could be obtained from cultures of bacteria (Bacillus r Streptomyces) or fungi (Penicillium,
  • Cephalosporium which are toxic to other microorganisms.
  • this term is also used to refer to synthetic compounds, that is, produced exclusively by chemical synthesis, or semi-synthetic ones, these being the ones obtained from a basic nucleus of an antibiotic produced by a microorganism, which is modifies its chemical structure to improve its pharmacokinetic properties, its spectrum, or even, to decrease its toxicity [6].
  • an antibiotic is a chemical produced by a living being or manufactured by synthesis, capable of paralyzing the development of certain pathogenic microorganisms, by their bacteriostatic action, or causing their death, by their bactericidal action [ 7]. Almost simultaneously with the discovery and use of antibiotics, bacterial resistance appeared.
  • a resistant strain or bacteria is defined as one that is capable of multiplying in the presence of concentrations greater than those reached with therapeutic doses [8]. Bacteria can develop resistance to antibiotics by spontaneous mutation or by the exchange of genes between strains and bacterial species [9]. Alexander Fleming was the first to warn about the potential importance of the emergence of resistance [10] and shortly thereafter alarming results were obtained, since in 1946, a UK hospital reported that 14% of Staphylococcus aureus infections were resistant to penicillin. Already in 1950, that proportion had increased to 59%. In the 1990s, the rate of resistance of S. aureus to penicillin had reached levels above 80% both in hospitals and in the community [11].
  • Antimicrobial resistance is referred in clinical settings mainly to measures for infection control and selective pressure of antimicrobial agents on a pathogen. Antimicrobial resistance is a problem that has transcended over time and is currently a public health problem [8], concrete examples of this is that currently multiresistant tuberculosis has been reported in 64 countries and every year they produce about 440,000 new cases that cause at least 150,000 deaths.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE Vancomycin resistant
  • Methicillin-resistant Staphylococcus aureus or MRSA is a mutant of the Staphylococcus aureus bacteria that has become resistant to several antibiotics, first to penicillin in 1947, and then to methicillin.
  • MRSA is acquired primarily in a hospital. Its most serious manifestations are sepsis, cellulitis and nosocomial pneumonia, a disease that can be fatal and is acquired mainly in patients with mechanical or assisted breathing. Pharmacologically, MRSA, like VRE, has responded to tartar with linezolid to help fight infection. On the other hand, VRE, to become a vancomycin-resistant bacterium, must typically obtain new DNA in the form of plasmids or transposons that encode genes that confer resistance to it. This acquired resistance is distinguished and is different from the natural vancomycin resistance of certain enterococcal species, including E. gallinarum and E. casseliflavus.
  • Van-A Van-B
  • Van-C Van-D
  • Van-E Van-G
  • Van-A VRE is resistant to both vancomycin and teicoplanin antibiotics
  • Van-B VRE is resistant to vancomycin but susceptible to teicoplanin
  • Van-C is only partially resistant to vancomycin, and susceptible to teicoplanin.
  • Biochemically the mechanism of vancomycin resistance for Enterococcus found involves the alteration of the peptidoglycan synthesis pathway.
  • the resulting D-alanyl-D-lactate decreases the interaction by the loss of a hydrogen bridge (four, as opposed to five for D-alanyl D-alanine) between vancomycin and the peptide.
  • the variation in D-alanyl-D-serine causes a six-fold loss of affinity between vancomycin and the peptide, thereby preventing the antibiotic from performing its function.
  • cephalosporins that would help colonization and VRE infection is considered a risk factor, and its restriction is associated with a decrease in VRE infections and their transmission in the hospitals
  • Bacteria such as Lactobacillus rhamnosus GG (LGG), a strain of L. rhamnosus, have been used to treat VRE infections.
  • Linezolid is usually used to treat VRE.
  • PBP 2a penicillin-binding protein
  • mee A a new gene called mee A and retains its action of transpeptidase in the synthesis of the bacterial wall even when the other PBPs of S. Aureus are inhibited by ⁇ -lactam drugs.
  • Stafiloccocus Aureus with intermediate vancomycin resistance mediated by Stafiloccocus Aureus with intermediate vancomycin resistance (VISA), or emerging strains with linezolid resistance of Stafiloccocus Aureus, or emerging strains with resistance to linezolid of emerging Enterococcus Faecalis with resistance and / or non-susceptible strains to daptomycin.
  • VSA vancomycin resistance
  • antimicrobial resistance is affecting even the latest generation of oral cephalosporins and its prevalence is increasing worldwide, so some treatments are being complemented, such as gonorrhea, so intractable gonococcal infections could increase the morbidity and mortality rates and if so, would nullify the advances made in the control of this sexually transmitted infection.
  • hydrolytic enzymes such as NDM-1 Metallobetalactamase
  • This may render several potent antibiotics ineffective, such as carbapenemic derived compounds, which are often used as a last defense against multiresistant bacterial strains [12].
  • the causes that have This hostile context has been facilitated and, in turn, they provide favorable conditions for the emergence and spread of resistant microorganisms are mainly the prescription of drugs both excessive (when an antibiotic is not required to prevent or in supraterapeutic doses) and insufficient (subtherapeutic doses) ; non-observance of the recommended doses; the lack of regulation of the sale [13]; inappropriate and irrational use of antibiotics, especially in livestock [14,15]; poor practices in the prevention and control of infections and, last but not least, the poor adherence to antibiotic treatments by patients, which in turn is the cause of the poor education provided to them regarding topic.
  • the mechanisms through which bacterial resistance operates are diverse, among which are: destruction or enzymatic inactivation of the antibiotic, modification of the pharmacological target, restriction of the entry of the antibiotic into the cell and active expulsion of the antibiotic before I acted [17].
  • the pressure of a certain antibiotic in a medium favors that the populations of bacteria with a resistance characteristic multiply and prevail in the environment since once the resistance is acquired, it can be passed vertically from mother to daughter bacteria, which originates clones with said resistance or horizontally to other bacteria by mechanisms of transformation, transduction, transposition or conjugation [16].
  • Examples of types of bacteria representative of the resistance generation process (ESKAPE pathogens, with current treatment but with a rapid loss of effectiveness of the same treatments) and bacteria that currently do not have antibiotic treatment are: Eschericha coli r Pseudomona aeruginosa r Staphylococcus aureus, Enterococcus faecalis r Enterobacter Spp. r Klebsiella Spp. and Acinetobacter baumannii, among new ones that appear year by year.
  • the unit to attack must be a common structure in multiple bacterial types, thus managing to cover a broad spectrum.
  • an antibacterial biological objective is the electron transport chain (CTe), with ubiquinone (UBQ) being essential for its operation, which allows the flow of electrons from complex I to complex III and from complex II to complex III [19].
  • Ce electron transport chain
  • UBQ ubiquinone
  • the functional blockage of this unit could produce a fall in the generation of ATP and progressive damage to bacterial viability [20].
  • ubiquinone corresponds to 2,3-dimethoxy-5-methyl-6-polyisoprenyl-1, 4-benzoquinone [21], so it is inferred that quinonic compounds could interfere with the electron transport chain by emulating the UBQ .
  • quinoid molecules have interesting electrochemical properties, being able to be reversibly reduced first to semiquinone and then to hydroquinone because of their ability to accept electrons [21], being compounds with the ability to capture and generate free radicals, and can generate an inappropriate redox medium for bacterial survival [22].
  • ROS reactive oxygen species
  • quinones that have excellent antibiotic properties, among which are: a) 7-methyl uglone, this compound has been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis [26]. b) Lapachol and its analogues have been used in the treatment of ringworm, diarrhea, gonorrhea, parasitic infections and as antifungals [27, 28]. c) Plumbagin shows activity against Staphylococcus aureus [29]. d) Juglone and 7-methyl uglone have activity against Streptococcus mutans and S. sanguis responsible for dental caries, and on Porphyromonas gingivalis and Prevotella intermedia causing gingivitis [30].
  • the present invention relates to quinonic derivative compounds of formula I, their isomers, their tautomers and / or their pharmaceutically acceptable salts, which are useful in the treatment of bacterial infections:
  • R is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl , phenyl, heterocycle and heteroaryl are: - CO-Z-C1-C15 alkyl, -Z-CO-C
  • R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , - SR 6 ; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; wherein heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, which has between 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: -H, - C1-C15 alkyl, C1-C15 substituted alkyl with R 7 ,
  • the present invention relates to the use of antibacterial agents derived from the pyrimido-isoquinolinquinone nucleus.
  • the compounds used in accordance with the present invention are comprised by the following structural formula I:
  • R is -H, -NH 2 , -OH, -SH, -NH-R, -N- (R) 2 , -0-R,
  • R is a C 1 -C 15 alkyl group, a substituted C 1 -C 15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C 1 - alkyl groups C15, aryl, phenyl, heterocycle and heteroaryl are: - CO-Z-C1-C15 alkyl, -Z-CO-C1-C15 alkyl, -H, -ter-butyl, - iso-propyl, -C1-C15 alkyl, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7
  • R 2 is -H, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 and halogen of the group Cl, Br, F and I ;
  • R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , - SR 6 ; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; wherein heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, which has between 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 6 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: -H, - C1-C15 alkyl, C1-C15 substituted alkyl with R 7 ,
  • a second preferred group of the compounds of the present invention includes compounds possessing formula I, wherein R is -NH- (CH 2 ) n-, -O- (CH 2 ) n -R, -S- (CH 2 ) n -R; where R is a substituted phenyl group, where the substitutions of the phenyl group are independently: -Z-CO-Ci - C15 alkyl, -CO-Z-C1-C15 alkyl, -H, -ter-butyl, -iso-propyl, -C1-C15 alkyl, -CF 3 , halogen of the group Cl, Br, F and I, -NH 2 , -N0 2 , - NH-R 7 , -N (R 7 ) 2, -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S
  • R is H; R 3 is H and C1-C15 alkyl, where R 4 and R 5 are H, a C1-C15 alkyl group.
  • R 2 is -H, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 ;
  • R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where the R 6 substitutions of the phenyl group are in ortho and para positions.
  • a fourth preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
  • R 3 is H, Ci-Ci 5 alkyl; where R 4 and R 5 are H, a C1-C15 alkyl group.
  • a fifth preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
  • n 0-8; where w is independently: O, N, SO 2 , SO, S, C or Si; where y, z and j are C or N; R z is -H;
  • R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where R 8, R 9, R 10 and R 11 are independently -H, - C1-C15 alkyl, substituted C1-C15 with R 7, halogen group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S -CF 3 , -ter-butyl, -iso-propyl and -CF 3 ; where R 7 is a group -H, C 1 -C 15 alkyl, -OH.
  • a sixth preferred group of the compounds of the present invention includes compounds possessing the formula where
  • R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are -H, a C 1 -C 15 alkyl group;
  • a seventh preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
  • n 0-8; where Z is independently: O, N, SO 2 , SO, S, C or Si; where Y is C or N; R 2 is -H;
  • R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group.
  • an eighth preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
  • n 0-8; where K, Z are independently: O, N, SO 2, SO, S, C or Si; where G, I, Y, J and W are independently: N or C; R is -H;
  • R 3 is -H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where R 9, R 10 and R 11 are independently -H, - C1-C15 alkyl, substituted alkyl C 1-C15 with R 7, halogen group Cl, Br, F and I, -NH 2, - N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 , -ter-butyl, -iso-propyl and -CF 3 ; where R 7 is a group -H, C 1 -C 15 alkyl, -OH.
  • halogen refers to fluorine, chlorine, bromine or iodine, unless otherwise indicated.
  • Alkyl refers to a linear, cyclic or branched hydrocarbon residue, preferably an alkyl group of 1 to 15 carbon atoms, unless otherwise indicated.
  • > cycloalkyl 'as used herein refers to a cyclic alkyl, for e. , cyclopropyl, unless otherwise indicated.
  • rile refers to a monocyclic or bicyclic aromatic group, in which each ring of the individual or fused ring system contains 6-12, preferably 6-10 cyclic atoms [sic], by e . , includes phenyl, naphthyl, biphenyl and indenyl, but is not always limited to these.
  • heterocycloalkyl refers to a cyclic alkyl, eg. , monocyclic or bicyclic alkyl, containing one or more heteroatoms, preferably one to four heteroatoms, selected from O, N and S, unless otherwise indicated.
  • monoheterocycloalkyl include piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and similar groups of the foregoing, although not limited thereto.
  • heterocycle within the > heterocycloalkyl ', is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring.
  • monocyclic heteroaryl examples include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups thereof, although these are not limited thereto, .
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, bencisoxazolyl, benzthiazolyl, benzothiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, furyl, furopyridinyl, oxyindole, similar to these, although they are similar to these.
  • heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, which has between 1 to 4 heteroatoms selected from N, O, and S.
  • the compounds of the present invention can also form a pharmaceutically acceptable salt.
  • Said salt may be an pharmaceutically acceptable non-toxic acid addition salt containing anion, although not limited thereto.
  • the salt may include addition salts with acids formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydric acid, and others; organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and others; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and others.
  • the compound of the present invention may have an asymmetric carbon center, and thus may be present in the form of an R or S isomer, racemic compounds, diasteromeric mixture, or individual diasteromer, said whole isomers and mixtures. included within the scope of the present invention
  • 6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4JJ) - tetraone 6-ethyl-2,4-dimethyl-8- (phenylthio) pyrimido [4 , 5-c] and soquinolin- 1,3,7,10 (2H, 4JJ) -tetraone
  • 6-ethyl-8- ((3-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
  • 6-ethyl-8- ( (3-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
  • 6-ethyl-8- ((4-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
  • 6-ethyl-8- ((4-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
  • 6-ethyl-8- ((4-fluorophenyl) amino) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 8- ((4-chlorophenyl) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 8- ((4-bromophenyl) ) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone methyl 4- ((6-ethyl-2, 4-dimethyl -l, 3,7, 10-tetraoxo-l, 2, 3,4,7,10-hexahydropyrimido [4,5-c] isoquinolin-8-yl) amino
  • the effective dose of the pyrimido-isoquinolinquinone derivatives represented by the formula I, its hydrates, its solvates or its salts accepted for pharmaceutical use can be determined considering the specific compounds used, the method of administration, the chosen individual, the chosen disease, etc., to carry out the
  • the daily dose can be administered once a day (at a time) or several times a day when properly divided into an effective daily dose.
  • oral administration parenteral administration is possible (injection) or local administration.
  • the pharmaceutical composition of the present invention can be formulated for oral administration as tablets, powders, dried syrups, chewable tablets, granules, capsules, soft capsules, pills, beverages, sublinguals, etc.
  • the composition of the invention formulated as tablets may be administered to an individual by any method or route that delivers the effective dose of the tablet with bioavailability, which may be the oral route. Also the method or route of administration can be determined according to the characteristics, stages of the target disease or other conditions.
  • the composition of the invention is formed as tablets, they may also include excipients accepted for use.
  • excipient can be determined by the solubility and chemical properties of the chosen tablet, the route of
  • compositions can be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional pharmaceutical excipients and / or additives, and by preparing unit dosage forms suitable for use as an antibiotic.
  • pharmaceutically acceptable additives may include a diluent, a binder, a disintegrant, and the like.
  • the diluent may include microcrystalline cellulose, lactose, mannitol, calcium phosphate, and the like;
  • the binder may include povidone, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose, and the like; and some examples of the disintegrant may include crospovidone, croscarmellose sodium, sodium starch glycolate, and the like.
  • additives or vehicles for oral formulations include cellulose, calcium silicate, corn starch, sucrose, dextrose, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents and others.
  • the diluent can be used in an amount ranging from 20 to 95% by weight
  • the binder can be used in an amount ranging from 1 to 10% by weight
  • the disintegrant can be used in an amount ranging from 1 to 30% in weight. weight, based on the total weight of the composition.
  • additives or vehicles such as water, saline solution, glucose solution, glucose solution analogues, alcohols, glycols, ethers (eg, polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents, and others, preferably, physiological saline solutions can be used as a major carrier.
  • the pH of said solutions should preferably be maintained between 6.5 and 7.2 with a suitable buffer system.
  • the formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preferred preservatives that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmecuric nitrate.
  • a preferred surfactant is, for example, Tween 80, without being limited thereto only.
  • various preferred vehicles may be used in the preparations herein. invention.
  • These vehicles include, but are not limited to, propylene glycol, sodium hydroxide solutions, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjusters can be added as necessary or convenient. They include, without limitation, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable and acceptable tonicity adjuster.
  • the buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers.
  • the acids or bases can be used to adjust the pH of these formulations as necessary.
  • an antioxidant acceptable for use in the present invention includes, without limitation, sodium metabisulphite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • Other excipient components in both liquid solution and oral composition, which can be included in the preparations are chelating agents.
  • chelating agents to be used can be mentioned ethylenediaminetetraacetate calcium and disodium (CaNa2EDTA), triethylenetetraminehexaacetic acid (TTHA), dihydroxyethylenediamine diacetic acid (hydroxyethylenediaminetriacetic acid (HEDTA), oxalate 1, its derivatives, oxalato (2) bis (diphenylphosphino) ethylene (DPPE) dimercaprol (BAL), diethylenetriaminepentaacetic acid (DTPA), preferably ethylenediaminetetraacetic acid (EDTA) is used, although other chelating agents may also be used instead or with said agent alone.
  • EDTA has a double function in this invention, on the one hand it is a chelating agent that tends to trap metal particles.On the other hand, EDTA has not been recognized as an antimicrobial agent, in general, it is considered as an "enhancer" of the activity of other antimicrobial agents (Brown and Richards 1965) As such, the literature has written about it an effect synergistic or common reinforcement to action with preservatives, antibiotics and cationic surfactants, for example, quaternary ammonium compounds (Weiser et al. 1969; Sheikh and Parker 1972; Hart 1984; Vaara 1992). Mechanically, one of the recognized modes of action of EDTA is the disruption of the lipopolysaccharide structure in the outer membrane of Gram-negative bacteria.
  • Microcrystalline cellulose (Avicel pH 10.1) 0-3, 0
  • reaction crude is purified with 50-90 g of 0.063-0.2 mm Silica gel using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase.
  • An orange solid, 288.7 mg, 0.66 mmol, is obtained in 66% yield.
  • reaction crude is purified with 50-90 g of Silica gel 0.063-0.2 rom using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase.
  • reaction crude is purified with 75 g of silica gel (0.040-0.063 mm) using mobile phase 4.0: 0.5: 0.5 petroleum ether: dichloromethane: ethyl acetate. An orange solid, 201.7 mg, 0.41 mmol, is obtained in 68.1% yield. Melting point 197.9 - 198.7 ° C.
  • a yellow-orange solid, 47.3 mg, 0.11 mmol, is obtained in 66% yield.
  • Example 36 Obtaining 8,9-bis (4-chlorothiophenyl) -6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (36) .
  • a colored solid is obtained yellow, 70.3 mg (0.1 mmol) with 26% yield.
  • R 3 is -H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2, -OR 6 , -SR 6 ; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 6 is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl, phenyl, heterocycle and heteroaryl are: - CO-Z-C1-C15 alkyl, -Z-CO-C1-C15 alkyl, -H, -ter-butyl, - iso-propyl, -C1-C15 alkyl, -CF 3 , halogen
  • This figure represents the electron transport chain (CTe).
  • A It is a representation of the normal flow of electrons through the CTe complexes, where the energy released from this flow of electrons is used for the translocation of protons against the gradient, which is an energetically unfavorable process.
  • the electrochemical gradient generated is used for the formation of ATP through an energy-efficient process.
  • This figure presents a graph showing the increase in resistance rates of three bacteria that are cause for concern for public health authorities: (MRSA), (VRE) and (FQRP).
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE Vancomycin Resistant Enterococci
  • FQRP Pseudomonas aeruginosa resistant to fluoroquinolones Figure 3/3
  • This figure shows a diagram above where the activity of the compound of example 16 of formula I against Gram (-) bacteria of the Echerichia Coli ATCC ⁇ 25922 type was verified.
  • the diagram below shows the activity of the compound of example 16 of formula I against Gram (-) bacteria of the Pseudomona Aeruginosa ATCC ⁇ 27853 type.
  • Bacteria used For the screening of antibacterial activity of the compound compounds a panel of prototype strains was used:
  • the compounds that were most active were tested on a panel of 89 clinical isolates of Gram-positive cocacceae isolated from different Chilean hospitals during 2014.
  • the isolates used were methicillin-resistant Staphylococcus aureus and Enterococcus spp. Vancomycin resistant that met a multi-resistance susceptibility profile defined by those isolates that presented resistance to at least one representative of 2 or more families of antibacterials.
  • the sites of origin of isolation were aspirated tracheal, wound and blood for Staphylococcus aureus, while the sites for Enterococcus spp were urine, peritoneal fluid, blood and wound.
  • the strains were sown from the cepary (where 50% v / v glycerol and Brain Heart Infusion culture broth, at -20 ° C) were stored in Mueller-Hinton agar (Oxoid, England).
  • the microdilution technique in culture broth was used according to the protocol suggested by the CLSI, briefly: In sterile 96-well culture plates (8 rows and 12 columns) (Ultracruz TM Polystyrene Microplates, 96 well, U bottom Santa Cruz biotechnology, inc.) 100 uL of Müeller Hinton broth was added in all wells, then added 100 uL of control or compound antibiotic to be tested in the 8 rows of the first column, to continue making serial dilutions with a dilution factor of 0.5. The concentrations to be tested range from 32 to 0.0625 g / mL. The wells of columns 11 and 12 were used for control Positive growth and sterility control respectively.
  • the plate was prepared, 100 uL of the bacterial suspension to be evaluated was previously adjusted to 0.5 Me Farland, in each of the wells excluding the wells in column 12. Finally, the plates were covered and incubated. at 36 ° C for 18 to 24 hours, after the time elapsed, the plates were observed using contrast light in order to determine the concentration at which bacterial growth is inhibited (indicated by the disappearance of turbidity).
  • the compounds of this invention are useful for the treatment of infectious diseases, preferably multiresistant to antibiotics in mammals, for example, humans.
  • the results obtained indicate that EDTA allows the antibiotic of formula I to act on Gram (-) strains in a concentration range between 10 to 800 g / ml, preferably in the range of 64 to 128 g / ml.

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Abstract

The present invention provides pyrimido-isoquinolin-quinone derivatives of formula (I), and pharmaceutically acceptable salts, isomers and tautomers thereof; a pharmaceutical composition; a preparation method; and use thereof in the treatment of diseases caused by bacteria and multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant Enterococcus spp. (VRE), Enterococcus faecalis, emerging linezolid-resistant Staphylococcus aureus and/or daptomycin-nonsusceptible bacterial strains, wherein the radicals R1, R2, R3, R4, and R5 are as defined in the description of the present invention.

Description

COMPUESTOS DERIVADOS PIRIMIDO-ISOQUINOLIN-QUINONAS , SUS SALES, ISOMEROS, TAUTOMEROS FARMACÉUTICAMENTE ACEPTABLES; COMPOSICIÓN FARMACÉUTICA; PROCEDIMIENTO DE PREPARACIÓN; Y SU USO EN EL TRATAMIENTO DE ENFERMEDADES BACTERIANAS Y BACTERIANAS MULTIRRESISTENTES. PIRIMIDO-ISOQUINOLIN-QUINONAS DERIVATIVE COMPOUNDS, THEIR SALTS, ISOMERS, PHARMACEUTICALLY ACCEPTABLE TAUTOMERS; PHARMACEUTICAL COMPOSITION; PREPARATION PROCEDURE; AND ITS USE IN THE TREATMENT OF MULTI-RESISTANT BACTERIAL AND BACTERIAL DISEASES.
Ambito de la invención. Field of the invention.
La presente invención se refiere a compuestos antibacterianos derivados un núcleo pirimido-isoquinolin- quinonas, procesos para su preparación, y los métodos para su uso . The present invention relates to antibacterial compounds derived from a pyrimido-isoquinolinquinone nucleus, processes for its preparation, and methods for its use.
Antecedentes de la invención. - Background of the invention. -
Descripción del arte relacionado. Description of the related art.
Antes del siglo XX, la medicina no contaba con las herramientas para combatir las enfermedades infecciosas, ya que ni siquiera se descubría una de las principales etiologías de estas dolencias, las bacterias. Antes del descubrimiento de los antibióticos una simple infección podía ser la razón de muerte de muchas personas. En efecto, por esta causa la mortalidad infantil era altísima, al igual que la mortalidad materna antes y después del parto. En el siglo XVII la mitad de la población de Europa murió por infecciones bacterianas [1] . La esperanza de vida en 1930 era de 35 a 40 años, actualmente este número ha aumentado considerablemente [2], y esto se debe en gran parte a la disponibilidad de antibióticos. Es por esto, que el descubrimiento de los antibióticos puede describirse como un hecho extraordinario que tiene sus inicios ligados a un gran investigador en microbiología, llamado Paul Ehrlich, quien tuvo una idea que para ese momento fue toda una revolución, la llamada "bala mágica" que tenía como objeto matar microorganismos dentro del individuo, pero sin causarle daño, allí estaba lo mágico. Este concepto nació a principios del siglo XX, cuando recientemente se había conocido la existencia de los microorganismos. Se cuentan más de 606 experimentos antes de que naciera la "bala mágica" llamada Salvarsan. Así, desde 1910 el Salvarsan apareció como el primer producto capaz de matar bacterias dentro del organismo humano, y se utilizaba para la sífilis, la buba y el pian, la cuales son enfermedades bacterianas. En 1914 se obtiene un producto más eficiente que el Salvarsan, el Neosalvarsan . Posteriormente se abre una nueva etapa con la obtención de las sulfonamidas, resultado de las investigaciones de Domagk [3] . Before the twentieth century, medicine did not have the tools to fight infectious diseases, since not even one of the main etiologies of these ailments, bacteria, was discovered. Before the discovery of antibiotics a simple infection could be the reason of death of many people. Indeed, for this cause infant mortality was very high, as was maternal mortality before and after childbirth. In the 17th century half of the population of Europe died from bacterial infections [1]. Life expectancy in 1930 was 35 to 40 years, currently this number has increased considerably [2], and this is due in large part to the availability of antibiotics. This is why the discovery of antibiotics can be described as an extraordinary fact that has its beginnings linked to a great researcher in microbiology, called Paul Ehrlich, who had an idea that by that time was a revolution, the so-called "magic bullet "which was intended to kill microorganisms within the individual, but without causing harm, there was the magic. This concept was born at the beginning of the 20th century, when the existence of microorganisms had recently been known. More than 606 experiments are counted before the "magic bullet" called Salvarsan was born. Thus, since 1910 Salvarsan appeared as the first product capable of killing bacteria within the human organism, and was used for syphilis, buba and pian, which are bacterial diseases. In 1914 a more efficient product is obtained than Salvarsan, the Neosalvarsan. Subsequently a new stage is opened with the obtaining of sulfonamides, the result of Domagk's research [3].
En 1929, Alexander Fleming observa que un hongo llamado Penicillium notatum, inhibe el crecimiento de las bacterias. No obstante, el investigador no termina su descubrimiento, al no demostrar la eficiencia de este hongo como "bala mágica". Dicho producto recibió el nombre de Penicilina y en 1940 se consolidó como el primer antibiótico gracias a la labor de Chain y Florey quienes finalmente consiguen aislar y confirmar los efectos de este agente [4] . Es por esto que la penicilina descubierta en 1929, tiene su nacimiento como antibiótico en 1940, fecha en la que se incorpora formalmente a la terapéutica humana. Posteriormente, durante la segunda guerra mundial surge el mejor laboratorio de experimentación para la penicilina y las sulfas, dado que es en ese contexto en donde se comenzaron a utilizar en cantidades importantes, quedando demostradas las bondades de estos agentes [3]. El advenimiento de las cefalosporinas fue también un gran avance en la terapia antibiótica. Cerca de la boca del desagüe en la Costa de Cerdeña, el italiano Giuseppe Brotzu de la Universidad de Cagliari aisló el nuevo beta-lactamico del "Cephalosporium acremonium", primera fuente de estos medicamentos. El descubrimiento posterior del núcleo activo de la cefalosporina C y la posibilidad de agregarle cadenas laterales hizo factible desarrollar nuevos compuestos semisintéticos con una actividad antibacteriana mucho mayor. Los macrólidos, efectivos contra Gram positivos, una alternativa en los pacientes alérgicos a la penicicilina, iniciaron su itinerario con la eritromicina; este antibiótico "efectivo por vía oral" es producido por el "S. Erythreus", cepa obtenida del suelo del archipiélago filipino [5] . Posteriormente se fueron desarrollando otros tipos de antibióticos, hasta llegar al arsenal con el que la medicina dispone actualmente. In 1929, Alexander Fleming observes that a fungus called Penicillium notatum inhibits the growth of bacteria. However, the researcher does not finish his discovery, by not demonstrating the efficiency of this fungus as a "magic bullet." This product received the name of Penicillin and in 1940 it was consolidated as the first antibiotic thanks to the work of Chain and Florey who finally manage to isolate and confirm the effects of this agent [4]. This is why penicillin discovered in 1929, has its birth as an antibiotic in 1940, when it is formally incorporated into human therapy. Subsequently, during the Second World War, the best laboratory for experimentation for penicillin and sulfa arises, given that it is in this context that they began to be used in significant quantities, demonstrating the benefits of these agents [3]. The advent of cephalosporins was also a breakthrough in antibiotic therapy. Near the mouth of the drain on the Sardinian Coast, the Italian Giuseppe Brotzu of the University of Cagliari isolated the new beta-lactam of "Cephalosporium acremonium", the first source of these drugs. The subsequent discovery of the active nucleus of cephalosporin C and the possibility of adding side chains made it possible to develop new semi-synthetic compounds with a much greater antibacterial activity. Macrolides, effective against Gram positive, an alternative in patients allergic to penicicillin, they started their itinerary with erythromycin; This "effective oral" antibiotic is produced by the "S. Erythreus" strain obtained from the soil of the Philippine archipelago [5]. Subsequently, other types of antibiotics were developed, until reaching the arsenal with which medicine currently has.
En un principio, el término antibiótico sólo se empleaba para referirse a los compuestos orgánicos de origen biológico, los cuales se podían obtener desde cultivos de bacterias (Bacillus r Streptomyces) u hongos ( Penicillium,Initially, the term antibiotic was only used to refer to organic compounds of biological origin, which could be obtained from cultures of bacteria (Bacillus r Streptomyces) or fungi (Penicillium,
Cephalosporium) , que resultan tóxicos para otros microorganismos. En la actualidad también se emplea este término para denominar a compuestos sintéticos, es decir, producidos exclusivamente por síntesis química, o semisintéticos , siendo estos los que se obtienen a partir de un núcleo básico de un antibiótico producido por un microorganismo, al cual se le modifica su estructura química para mejorar sus propiedades farmacocinéticas , su espectro, o incluso, para disminuir su toxicidad [6] . Según la Real Academia Española, un antibiótico es una sustancia química producida por un ser vivo o fabricada por síntesis, capaz de paralizar el desarrollo de ciertos microorganismos patógenos, por su acción bacteriostática, o de causar la muerte de ellos, por su acción bactericida [7] . Casi simultáneamente al descubrimiento y uso de los antibióticos, apareció la resistencia bacteriana. Una cepa o bacteria resistente se define como aquella que es capaz de multiplicarse en presencia de concentraciones mayores que las alcanzadas con dosis terapéuticas [8]. Las bacterias pueden desarrollar resistencia a los antibióticos por mutación espontánea o por el intercambio de genes entre cepas y especies bacterianas [9] . Alexander Fleming fue el primero en advertir sobre la importancia potencial de la aparición de resistencia [10] y poco tiempo después se obtuvieron resultados alarmantes, ya que en 1946, un hospital del Reino Unido informó que el 14% de las infecciones por Staphylococcus aureus eran resistentes a la penicilina. Ya en 1950, esa proporción había aumentado a un 59%. En los años noventa, la tasa de resistencia de S. aureus a la penicilina había alcanzado niveles superiores al 80% tanto en los hospitales como en la comunidad [11] . La resistencia a antimicrobianos es referida en el ámbito clínico principalmente a las medidas para el control de la infección y la presión selectiva de los agentes antimicrobianos sobre un patógeno. La resistencia antimicrobiana es un problema que ha trascendido en el tiempo y en el presente es un problema de salud pública [8], ejemplos concretos de esto es que en la actualidad se ha notificado en 64 países la tuberculosis multirresistente y cada año se producen unos 440.000 casos nuevos que causan como mínimo 150.000 defunciones. Cephalosporium), which are toxic to other microorganisms. At present, this term is also used to refer to synthetic compounds, that is, produced exclusively by chemical synthesis, or semi-synthetic ones, these being the ones obtained from a basic nucleus of an antibiotic produced by a microorganism, which is modifies its chemical structure to improve its pharmacokinetic properties, its spectrum, or even, to decrease its toxicity [6]. According to the Royal Spanish Academy, an antibiotic is a chemical produced by a living being or manufactured by synthesis, capable of paralyzing the development of certain pathogenic microorganisms, by their bacteriostatic action, or causing their death, by their bactericidal action [ 7]. Almost simultaneously with the discovery and use of antibiotics, bacterial resistance appeared. A resistant strain or bacteria is defined as one that is capable of multiplying in the presence of concentrations greater than those reached with therapeutic doses [8]. Bacteria can develop resistance to antibiotics by spontaneous mutation or by the exchange of genes between strains and bacterial species [9]. Alexander Fleming was the first to warn about the potential importance of the emergence of resistance [10] and shortly thereafter alarming results were obtained, since in 1946, a UK hospital reported that 14% of Staphylococcus aureus infections were resistant to penicillin. Already in 1950, that proportion had increased to 59%. In the 1990s, the rate of resistance of S. aureus to penicillin had reached levels above 80% both in hospitals and in the community [11]. Antimicrobial resistance is referred in clinical settings mainly to measures for infection control and selective pressure of antimicrobial agents on a pathogen. Antimicrobial resistance is a problem that has transcended over time and is currently a public health problem [8], concrete examples of this is that currently multiresistant tuberculosis has been reported in 64 countries and every year they produce about 440,000 new cases that cause at least 150,000 deaths.
Otras infecciones multirresistentes de origen intrahospitalario se da por patógenos, tales como, el Staphylococcus aureus resistentea la meticilina (SARM) o Enterococcus spp. resistente a la vancomicina (VRE) . Other multiresistant infections of in-hospital origin are caused by pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus spp. Vancomycin resistant (VRE).
El Staphylococcus aureus resistente a la meticilina o SARM es una mutante de la bacteria Staphylococcus aureus que se ha vuelto resistente a varios antibióticos, primero a la penicilina en 1947, y luego a la meticilina. Methicillin-resistant Staphylococcus aureus or MRSA is a mutant of the Staphylococcus aureus bacteria that has become resistant to several antibiotics, first to penicillin in 1947, and then to methicillin.
Si bien una colonización de SARM en un individuo por lo demás sano generalmente no es grave, la infección de esta bacteria puede amenazar la vida del paciente hospitalario, con heridas profundas o con su sistema inmunitario debilitado. Although a colonization of MRSA in an otherwise healthy individual is generally not serious, infection of this bacterium can threaten the life of the hospital patient, with deep wounds or with his weakened immune system.
El SARM se adquiere principalmente en un hospital. Sus manifestaciones más graves son la sepsis, celulitis y la neumonía nosocomial, enfermedad que puede son mortales y que se adquiere principalmente en los pacientes con respiración asistida o mecánica. Farmacológicamente, el SARM al igual que el VRE, han respondido al tartamiento con linezolid para ayudan a combatir la infección. Por otro lado, el VRE, para llegar a ser una bacteria resistente a la vancomicina debe obtener típicamente nuevo ADN en forma de plásmidos o transposones que codifican genes que confieren resistencia a la misma. Esta resistencia adquirida se distingue y es diferente de la resistencia a la vancomicina natural de ciertas especies de enterococos, incluyendo E. gallinarum y E. casseliflavus. MRSA is acquired primarily in a hospital. Its most serious manifestations are sepsis, cellulitis and nosocomial pneumonia, a disease that can be fatal and is acquired mainly in patients with mechanical or assisted breathing. Pharmacologically, MRSA, like VRE, has responded to tartar with linezolid to help fight infection. On the other hand, VRE, to become a vancomycin-resistant bacterium, must typically obtain new DNA in the form of plasmids or transposons that encode genes that confer resistance to it. This acquired resistance is distinguished and is different from the natural vancomycin resistance of certain enterococcal species, including E. gallinarum and E. casseliflavus.
La primera documentación sobre resistencia a la vancomicina E. faecalis y E. faecium con aislamientos clínicos de las cepas, se realizo en la década de 1980, en los Estados Unidos . The first documentation on vancomycin resistance E. faecalis and E. faecium with clinical isolates of the strains was made in the 1980s, in the United States.
Mecanisticamente la resistencia adquirida a la vancomicina se clasifica en seis tipos diferentes de resistencia para Enterococcus spp . : Van-A, Van-B, Van-C, Van-D, Van-E y Van-G [9] El significado es que Van-A VRE es resistente a ambos antibióticos vancomicina y teicoplanina, Van-B VRE es resistente a la vancomicina pero susceptible a la teicoplanina y Van-C es sólo parcialmente resistente a la vancomicina, y susceptible a la teicoplanina. Bioquímicamente el mecanismo de resistencia a la vancomicina para Enterococcus encontrado implica la alteración de la vía de síntesis peptidoglicano . El D-alanil-D-lactato resultante hace disminuir la interacción por la pérdida de un puente de hidrógeno (cuatro, en contraposición a cinco para D- alanil D-alanina) entre la vancomicina y el péptido. La variación en la D-alanil-D-serina causa una pérdida de seis veces de la afinidad entre la vancomicina y el péptido, con lo cual se evita que el antibiótico realice su función. Mechanically acquired vancomycin resistance is classified into six different types of resistance for Enterococcus spp. : Van-A, Van-B, Van-C, Van-D, Van-E and Van-G [9] The meaning is that Van-A VRE is resistant to both vancomycin and teicoplanin antibiotics, Van-B VRE is resistant to vancomycin but susceptible to teicoplanin and Van-C is only partially resistant to vancomycin, and susceptible to teicoplanin. Biochemically the mechanism of vancomycin resistance for Enterococcus found involves the alteration of the peptidoglycan synthesis pathway. The resulting D-alanyl-D-lactate decreases the interaction by the loss of a hydrogen bridge (four, as opposed to five for D-alanyl D-alanine) between vancomycin and the peptide. The variation in D-alanyl-D-serine causes a six-fold loss of affinity between vancomycin and the peptide, thereby preventing the antibiotic from performing its function.
En general para el tratamiento de la infección por VRE, se considera como un factor de riesgo el uso de cefalosporinas que ayudarían en la colonización e infección por VRE, y su restricción se asocia con una disminución de las infecciones por VRE y su transmisión en los hospitales. Se han utilizado bacterias como el Lactobacillus rhamnosus GG (LGG) , una cepa de L. rhamnosus, para tratar infecciones VRE. Normalmente se utiliza linezolid para tratar VRE. In general for the treatment of VRE infection, the use of cephalosporins that would help colonization and VRE infection is considered a risk factor, and its restriction is associated with a decrease in VRE infections and their transmission in the hospitals Bacteria such as Lactobacillus rhamnosus GG (LGG), a strain of L. rhamnosus, have been used to treat VRE infections. Linezolid is usually used to treat VRE.
Por otro lado, el mecanismo de resistencia del SARM involucra la síntesis de una nueva proteína fijadora de penicilina (PBP) , denominada PBP 2a (o PBP) con afinidad baja para los fármacos β-lactámicos . Esta es codificada por un nuevo gen denominado mee A y conserva su acción de transpeptidasa en la síntesis de la pared bacteriana aún cuando las otras PBP del S . aureus estén inhibidas por fármacos β-lactámicos . Otras infecciones bacterianas con multirresistencia son mediadas por Stafiloccocus Aureus con intermedia resistencia a la vancomicina (VISA) , o cepas emergentes con resistencia a linezolid de Stafiloccocus Aureus, o cepas emergentes con resistencia a linezolid de Enterococcus Faecalis emergentes con resitencia y/o cepas no susceptibles a daptomicina. On the other hand, the mechanism of MRSA resistance involves the synthesis of a new penicillin-binding protein (PBP), called PBP 2a (or PBP) with low affinity for β-lactam drugs. This is encoded by a new gene called mee A and retains its action of transpeptidase in the synthesis of the bacterial wall even when the other PBPs of S. Aureus are inhibited by β-lactam drugs. Other bacterial infections with multidrug resistance are mediated by Stafiloccocus Aureus with intermediate vancomycin resistance (VISA), or emerging strains with linezolid resistance of Stafiloccocus Aureus, or emerging strains with resistance to linezolid of emerging Enterococcus Faecalis with resistance and / or non-susceptible strains to daptomycin.
Adicionalmente, la resistencia antimicrobiana está afectando incluso a la última generación de cefalosporinas orales y su prevalencia está en aumento en todo el mundo por lo que algunos tratamientos se están comple izando, como el de la gonorrea, por lo que las infecciones gonocócicas intratables podrían aumentar las tasas de morbilidad y mortalidad y de ser así, anularían los avances realizados en el control de esta infección de transmisión sexual. Además, ha aparecido resistencia a travéz de enzimas hidrolíticas , como la Metalobetalactamasa NDM-1, en varios bacilos Gram negativos. Esto puede volver ineficaces varios antibióticos potentes, tales como los compuestos derivados carbapenémicos , que a menudo se utilizan como última defensa frente a cepas bacterianas multirresistentes [12] . Las causas que han facilitado este hostil contexto y, que a su vez, proporcionan condiciones favorables para la aparición y propagación de microorganismos resistentes son principalmente la prescripción de fármacos tanto excesiva (cuando no es requerido un antibiótico para prevenir o en dosis supraterapéuticas ) como insuficiente (dosis subterapéuticas ) ; la inobservancia de las dosis recomendadas; la falta de regulación de la venta [13]; el uso inadecuado e irracional de los antibióticos, especialmente en la ganadería [14, 15]; las prácticas deficientes en materia de prevención y control de las infecciones y por último, pero muy importante, la escasa adherencia a los tratamientos antibióticos por parte de los pacientes, que es causa a su vez de la poca educación que se les proporciona con respecto al tema. El impacto de la resistencia antimicrobiana es descomunal para la salud de la población, ya que conlleva a que se aumente la duración de las infecciones y aumenta el riesgo de muerte, poniendo en peligro el control de las enfermedades infecciosas al reducir la eficacia de los tratamientos, es decir, amenaza a retroceder a la época anterior al descubrimiento de los antimicrobianos. Pese a todos estos antecedentes, cada vez son menos los antibióticos nuevos que se crean [13] complicando aún más la situación . La resistencia de las bacterias a los antibióticos es una consecuencia previsible de la variación genética; al administrar un antibiótico se ejerce una presión selectiva sobre las bacterias de manera tal que éstas se ven, por supervivencia, forzadas a adaptarse [16] . En consecuencia, los mecanismos a través de los cuales opera la resistencia bacteriana son diversos, entre los que destacan: destrucción o inactivación enzimática del antibiótico, modificación del blanco farmacológico, la restricción de la entrada del antibiótico a la célula y la expulsión activa del antibiótico antes de que actué [17] . Finalmente, la presión de un determinado antibiótico en un medio favorece que las poblaciones de bacterias con una característica de resistencia se multipliquen y prevalezcan en el ambiente ya que una vez adquirida la resistencia, ésta puede pasarse verticalmente de bacteria madre a hija, lo cual origina clones con dicha resistencia u horizontalmente a otras bacterias por mecanismos de transformación, transducción, transposición o conjugación [16] . Additionally, antimicrobial resistance is affecting even the latest generation of oral cephalosporins and its prevalence is increasing worldwide, so some treatments are being complemented, such as gonorrhea, so intractable gonococcal infections could increase the morbidity and mortality rates and if so, would nullify the advances made in the control of this sexually transmitted infection. In addition, resistance has appeared through hydrolytic enzymes, such as NDM-1 Metallobetalactamase, in several Gram-negative bacilli. This may render several potent antibiotics ineffective, such as carbapenemic derived compounds, which are often used as a last defense against multiresistant bacterial strains [12]. The causes that have This hostile context has been facilitated and, in turn, they provide favorable conditions for the emergence and spread of resistant microorganisms are mainly the prescription of drugs both excessive (when an antibiotic is not required to prevent or in supraterapeutic doses) and insufficient (subtherapeutic doses) ; non-observance of the recommended doses; the lack of regulation of the sale [13]; inappropriate and irrational use of antibiotics, especially in livestock [14,15]; poor practices in the prevention and control of infections and, last but not least, the poor adherence to antibiotic treatments by patients, which in turn is the cause of the poor education provided to them regarding topic. The impact of antimicrobial resistance is huge for the health of the population, since it leads to an increase in the duration of infections and increases the risk of death, jeopardizing the control of infectious diseases by reducing the effectiveness of treatments , that is, it threatens to go back to the time before the discovery of antimicrobials. Despite all these antecedents, there are fewer and fewer new antibiotics that are created [13] complicating the situation even more. The resistance of bacteria to antibiotics is a predictable consequence of genetic variation; When administering an antibiotic, a selective pressure is exerted on the bacteria in such a way that they are, for survival, forced to adapt [16]. Consequently, the mechanisms through which bacterial resistance operates are diverse, among which are: destruction or enzymatic inactivation of the antibiotic, modification of the pharmacological target, restriction of the entry of the antibiotic into the cell and active expulsion of the antibiotic before I acted [17]. Finally, the pressure of a certain antibiotic in a medium favors that the populations of bacteria with a resistance characteristic multiply and prevail in the environment since once the resistance is acquired, it can be passed vertically from mother to daughter bacteria, which originates clones with said resistance or horizontally to other bacteria by mechanisms of transformation, transduction, transposition or conjugation [16].
Ejemplos de tipos de bacterias representativas del proceso de generación de resistencias (patógenos ESKAPE, con tratamiento actual pero con una rápida perdida de efectividad de los mismos tartamientos ) y de bacterias que en este momento no tienen tratamiento antibiótico son: Eschericha coli r Pseudomona aeruginosa r Staphylococcus aureus, Enterococcus faecalis r Enterobacter Spp. r Klebsiella Spp. y Acinetobacter baumannii, entre otras nuevas que aparecen año por año. En la actualidad, los antibióticos disponibles poseen blancos tradicionales que apuntan fundamentalmente a la síntesis de la pared celular bacteriana, a la síntesis de proteínas o la replicación del ADN, permitiendo que antibióticos que no están relacionados estructuralmente, en ocasiones posean objetivos comunes, siendo justamente las mutaciones en estos objetivos comunes las que se dan con mayor frecuencia en las bacterias que son resistentes a múltiples antibióticos [18]. Por consiguiente, es trascendental desarrollar nuevos antibióticos que puedan evadir las resistencias conocidas actualmente y/o que ataquen nuevos blancos. En cuanto a este último punto, para evitar la resistencia bacteriana, la elección de estos nuevos targets debe hacerse en función de tres parámetros: 1. El blanco antimicrobiano debe ser esencial para la sobrevida de la bacteria, por lo que al dejar no funcional esta unidad, sea altamente probable la muerte del microorganismo . 2. El objetivo o target debe ser conservado en el tiempo, es decir, con baja tasa de mutagenisidad, resultando más complejo para la bacteria desarrollar cambios que conduzcan a evadir el agente antimicrobiano. Examples of types of bacteria representative of the resistance generation process (ESKAPE pathogens, with current treatment but with a rapid loss of effectiveness of the same treatments) and bacteria that currently do not have antibiotic treatment are: Eschericha coli r Pseudomona aeruginosa r Staphylococcus aureus, Enterococcus faecalis r Enterobacter Spp. r Klebsiella Spp. and Acinetobacter baumannii, among new ones that appear year by year. Currently, available antibiotics have traditional targets that primarily target the synthesis of the bacterial cell wall, protein synthesis or DNA replication, allowing antibiotics that are not structurally related, sometimes have common goals, being precisely mutations in these common goals are those that occur most frequently in bacteria that are resistant to multiple antibiotics [18]. Therefore, it is transcendental to develop new antibiotics that can evade the currently known resistance and / or attack new targets. Regarding this last point, in order to avoid bacterial resistance, the choice of these new targets must be based on three parameters: 1. The antimicrobial target must be essential for the survival of the bacteria, so leaving this non-functional is unit, the death of the microorganism is highly probable. 2. The objective or target must be preserved over time, that is, with a low rate of mutagenisity, resulting in more complex bacteria to develop changes that lead to evading the antimicrobial agent.
3. La unidad a atacar debe ser una estructura común en múltiples tipos bacterianos, logrando asi abarcar un amplio espectro . A la luz de estos parámetros, un objetivo biológico antibacteriano es la cadena transportadora de electrones (CTe) , siendo esencial para su funcionamiento la ubiquinona (UBQ) , la cual permite el flujo de electrones del complejo I al complejo III y del complejo II al complejo III [19] . El bloqueo funcional de esta unidad podría producir una caída en la generación de ATP y un daño progresivo en la viabilidad bacteriana [20]. 3. The unit to attack must be a common structure in multiple bacterial types, thus managing to cover a broad spectrum. In light of these parameters, an antibacterial biological objective is the electron transport chain (CTe), with ubiquinone (UBQ) being essential for its operation, which allows the flow of electrons from complex I to complex III and from complex II to complex III [19]. The functional blockage of this unit could produce a fall in the generation of ATP and progressive damage to bacterial viability [20].
Químicamente, la ubiquinona corresponde a la 2 , 3-dimetoxi- 5-metil-6-poliisoprenil-l, 4-benzoquinona [21], por lo que se infiere que compuestos quinónicos podrían interferir con la cadena transportadora de electrones al emular la UBQ. Chemically, ubiquinone corresponds to 2,3-dimethoxy-5-methyl-6-polyisoprenyl-1, 4-benzoquinone [21], so it is inferred that quinonic compounds could interfere with the electron transport chain by emulating the UBQ .
Figure imgf000016_0001
Figure imgf000016_0001
Estructura general de la ubiquinona  General structure of ubiquinone
Cabe señalar, además, que las moléculas quinoides cuentan con interesantes propiedades electroquímicas, pudiendo reducirse en forma reversible primero a semiquinona y luego a hidroquinona por su capacidad de aceptar electrones [21], siendo compuestos con capacidad de capturar y generar radicales libres, pudiendo generar un medio redox inadecuado para la sobrevida bacteriana [22] . It should also be noted that quinoid molecules have interesting electrochemical properties, being able to be reversibly reduced first to semiquinone and then to hydroquinone because of their ability to accept electrons [21], being compounds with the ability to capture and generate free radicals, and can generate an inappropriate redox medium for bacterial survival [22].
Es interesante señalar que existe un equilibrio entre las tres especies quinoides (quinona, semiquinona e hidroquinona) , prevaleciendo la más estable, tal como se presenta a continuación : It is interesting to note that there is a balance between the three quinoid species (quinone, semiquinone and hydroquinone), with the most stable prevailing, as presented below:
Figure imgf000017_0001
Figure imgf000017_0001
Bajo este ángulo, se podría especular que si se introduce en el sistema de la cadena transportadora de electrones, otra molécula, similar a la UBQ, que tenga la capacidad de aceptar electrones y a su vez también de cederlos eficientemente, no al complejo III, sino que a otro aceptor que se encuentre en el sistema, como lo es el oxígeno molecular (O2) , se podría inducir la generación de especies reactivas de oxigeno (ROS del inglés Reactive Oxigen Species) . Esto, sumado al ROS que se producen de manera natural en la cadena transportadora de electrones bacteriana, puede llevar a daño progresivo de estructuras de soporte, sustratos, proteínas, enzimas o material genético de la bacteria perdiendo su viabilidad y muriendo [22, 23, dado que está ampliamente documentado que las especies reactivas de oxígeno tienen un papel clave en la génesis de la apoptosis [24] . Sin embargo, dado que tanto células bacterianas como humanas utilizan la cadena transportadora de electrones (CTe) para obtener energía en forma de ATP, podríamos estar en frente de un problema de toxicidad, no obstante, existen diferencias morfológicas entre células humanas y bacterianas que podrían otorgar selectividad por bacterias ya que, en el caso de éstas, la cadena de transporte de electrones se encuentran en la membrana plasmática. En cambio, en los seres humanos, se encuentra en la membrana interna de la mitocondria [19] . Por lo tanto, al variar la lipofilicidad de una molécula antibiótica que tenga como target la cadena trasportadora de electrones, se puede, a su vez, manipular que ésta quede atrapada en la primera barrera con la que se encuentre, siendo en el caso de bacterias el lugar en donde está ubicada la cadena trasportadora de electrones, en células humanas, en contraste, no lograría llegar a ella, dado que para esto deberá atravesar más barreras hasta llegar a la mitocondria. Under this angle, it could be speculated that if another molecule, similar to the UBQ, is introduced into the system of the electron transport chain, which has the ability to accept electrons and in turn also yield them efficiently, not to complex III, but that to another acceptor that is in the system, such as molecular oxygen (O2), the generation of reactive oxygen species (ROS of the English Reactive Oxigen Species) could be induced. This, added to the ROS that occur naturally in the bacterial electron transport chain, can lead to progressive damage of support structures, substrates, proteins, enzymes or genetic material of the bacteria losing their viability and dying [22, 23, Since it is widely documented that reactive oxygen species have a key role in the genesis of apoptosis [24]. However, since both bacterial and human cells use the electron transport chain (CTe) to obtain energy in the form of ATP, we could face a toxicity problem, however, there are morphological differences between human and bacterial cells that could grant selectivity for bacteria since, in the case of these, the electron transport chain is in the plasma membrane. In contrast, in humans, it is found in the inner membrane of the mitochondria [19]. Therefore, by varying the lipophilicity of an antibiotic molecule whose target is the electron transport chain, it can, in turn, be manipulated that it is trapped in the first barrier it encounters, being in the case of bacteria the place where the electron transport chain is located, in human cells, in contrast, would not be able to reach it, since for this it will have to cross more barriers until it reaches the mitochondria.
Considerando que para el funcionamiento de la CTe es esencial la ubiquinona y esta a su vez cumple con los tres parámetros ya mencionados de un blanco antibiótico eficiente, se infiere que usar esta unidad como objetivo o target antibacteriano, a través de moléculas que la imiten, podría ser una buena solución para combatir cepas resistentes. Las quinonas son un segundo grupo químico de compuestos que se encuentran en etapa de investigación preclinica y clínica debido a la gran diversidad de propiedades biológicas descritas, destacándose como antiparasitarios, antibacterianos, anticancerígenos y antifúngicos . [25] Considering that ubiquinone is essential for the operation of CTe and this in turn meets the three parameters already mentioned of an efficient antibiotic target, it is inferred that using this unit as an antibacterial target or target, through molecules that mimic it, It could be a good solution to fight resistant strains. Quinones are a second chemical group of compounds that are in the preclinical and clinical research stage due to the great diversity of biological properties described, standing out as antiparasitic, antibacterial, anticancer and antifungal. [25]
Existen ciertas quinonas que poseen excelentes propiedades antibióticas , entre las que destacan: a) La 7-metil uglona, este compuesto ha demostrado tener un potencial terapéutico, en particular contra Mycobacterium tuberculosis [26]. b) El lapachol y sus análogos se han utilizado en el tratamiento de la tiña, diarrea, gonorrea, infecciones parasitarias y como antifúngicos [27, 28] . c) La plumbagina muestra actividad contra Staphylococcus aureus [29] . d) La juglona y 7-metil uglona presentan actividad contra Streptococcus mutans y S. sanguis responsables de caries dental, y sobre Porphyromonas gingivalis y Prevotella intermedia causantes de gingivitis [30]. e) La 5-amino-8-hidroxi-l , 4-naftoquinona posee actividad frente a S. aureus, S. intermedius y S. epidermidis [31] . f) La 5, 8-dihidroxi-l , 4-naftoquinona es activa frente a especies de micobacterias [32]. g) Los derivados azufrados de la naftoquinona con sustitución p-anisidilo muestran actividad contra Streptococcus faecalis y Klebsiella pneumoniae y los compuestos con sustitución o-anisidilo, fenilo y metilo, presentan actividad antimicrobiana contra Escherichia coli [32] . h) y i) La 8-hidroxi-2- ( 1-hidroxietil ) nafto [ 2 , 3-b] furano- 4,9-diona, análogo cíclico del lapachol, se ha reportado como agente antibacteriano, mostrando actividad contra Helicobacter pilori, Staphylococcus , Enterococcus, Bacillus y Clostridium [33, 34] . Estructuralmente se ven a continuación las estructuras de los fármacos mencionados previamente: There are certain quinones that have excellent antibiotic properties, among which are: a) 7-methyl uglone, this compound has been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis [26]. b) Lapachol and its analogues have been used in the treatment of ringworm, diarrhea, gonorrhea, parasitic infections and as antifungals [27, 28]. c) Plumbagin shows activity against Staphylococcus aureus [29]. d) Juglone and 7-methyl uglone have activity against Streptococcus mutans and S. sanguis responsible for dental caries, and on Porphyromonas gingivalis and Prevotella intermedia causing gingivitis [30]. e) 5-Amino-8-hydroxy-l, 4-naphthoquinone has activity against S. aureus, S. intermedius and S. epidermidis [31]. f) 5,8-dihydroxy-l, 4-naphthoquinone is active against mycobacterial species [32]. g) Sulfur derivatives of naphthoquinone with p-anisidyl substitution show activity against Streptococcus faecalis and Klebsiella pneumoniae and the compounds with o-anisidyl, phenyl and methyl substitution have antimicrobial activity against Escherichia coli [32]. h) and i) 8-hydroxy-2- (1-hydroxyethyl) naphtho [2,3-b] furan-4,9-dione, cyclic analogue of lapachol, has been reported as an antibacterial agent, showing activity against Helicobacter pilori, Staphylococcus, Enterococcus, Bacillus and Clostridium [33, 34]. Structurally, the structures of the drugs mentioned above are shown below:
Figure imgf000021_0001
Figure imgf000021_0001
Otros antibacterianos descritos en el estado del arte son los presentados en las patentes WO 02/102793, WO2005/049605, WO2005/026104 donde se declaran compuestos antibióticos derivados de pirido pirimidinas . Other antibacterials described in the state of the art are those presented in patents WO 02/102793, WO2005 / 049605, WO2005 / 026104 where antibiotic compounds derived from pyrimidine pyrido are declared.
Situándonos en un contexto global, la propagación de las cepas resistentes en los últimos 30 años, según el Centro de Control y Prevención de las Enfermedades, ha tenido un crecimiento constante, tal como puede observarse en la figura 2/3. Resumen de la invención Placing ourselves in a global context, the spread of resistant strains in the last 30 years, according to the Center for Disease Control and Prevention, has grown steadily, as can be seen in Figure 2/3. Summary of the Invention
La presente invención se refiere a compuestos derivados quinónicos de formula I, sus isómeros, sus tautómeros y/o sus sales farmacéuticamente aceptables, que són útiles en el tratamiento de infeciones bacterianas: The present invention relates to quinonic derivative compounds of formula I, their isomers, their tautomers and / or their pharmaceutically acceptable salts, which are useful in the treatment of bacterial infections:
Figure imgf000022_0001
Figure imgf000022_0001
donde : where :
Figure imgf000022_0002
Figure imgf000023_0001
Figure imgf000022_0002
Figure imgf000023_0001
-S-R , -SO-R , -S02-R , -alquilo C1-C15, -Si-R , -SiO-R , -NH- (CH2)n-R6, -N( (CH2)n-R6)2' -0- (CH2)n-R6, -S- (CH2) n-R6' -Si- (CH2) n-R6; donde R es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: - CO-Z-alquilo C1-C15, -Z-CO-alquilo C1-C15, -H, -ter-butilo, - iso-propilo, -alquilo C1-C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7, -N (R7) 2, -C00H, -C00-R7, -0C0-R7, - 0-R7,-CN, -S-R7, -S-CF3 y fenilo sustituido a su vez con -H, - alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -C00H, -C00-R7, -0C0-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R es un grupo -H, alquilo C1-C15, -OH; donde X es O, N o S; donde n= 0-14; donde m= 0-14; donde 0= 1-14; donde K, Z, P, G, I, Y, J y W son independientemente: O, N, S02, SO, S, C o Si; R2 es -H, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6 y halógeno del grupo de Cl, Br, F y I; -SR, -SO-R, -S0 2 -R, -C1-C15 alkyl, -Si-R, -SiO-R, -NH- (CH 2 ) n -R 6 , -N ((CH 2 ) n -R 6 ) 2 '-0- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 ' -Si- (CH 2 ) n -R 6 ; where R is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl , phenyl, heterocycle and heteroaryl are: - CO-Z-C1-C15 alkyl, -Z-CO-C1-C15 alkyl, -H, -ter-butyl, - iso-propyl, -C1-C15 alkyl, -CF 3 , halogen of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 and phenyl substituted in turn with -H, - C1-C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 ; where R is a group -H, C1-C15 alkyl, -OH; where X is O, N or S; where n = 0-14; where m = 0-14; where 0 = 1-14; where K, Z, P, G, I, Y, J and W are independently: O, N, S0 2 , SO, S, C or Si; R 2 is -H, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 and halogen of the group Cl, Br, F and I ;
R3 es H, alquilo C1-C15, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, - S-R6; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo ; donde heteroarilo se define como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: -H, - alquilo C1-C15, alquilo sustituido C1-C15 con R7, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO- R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, -ter-butilo, -iso-propilo y -CF3. R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , - SR 6 ; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; wherein heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, which has between 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: -H, - C1-C15 alkyl, C1-C15 substituted alkyl with R 7 , halo of the group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 , -ter-butyl, -iso-propyl and -CF 3 .
Descripción detallada de la invención. Detailed description of the invention.
La presente invención se refiere al uso de agentes antibacterianos derivados del núcleo pirimido-isoquinolin- quinona. Los compuestos utilizados de acuerdo con la presente invención están comprendidos por la siguiente fórmula estructural I :
Figure imgf000026_0001
The present invention relates to the use of antibacterial agents derived from the pyrimido-isoquinolinquinone nucleus. The compounds used in accordance with the present invention are comprised by the following structural formula I:
Figure imgf000026_0001
donde : where :
R es -H, -NH2, -OH, -SH, -NH-R , -N-(R )2, -0-R , R is -H, -NH 2 , -OH, -SH, -NH-R, -N- (R) 2 , -0-R,
Figure imgf000026_0002
Figure imgf000026_0002
-SO-R , -S02-R , -Si-R , -SiO-R , -NH- (CH2) n- , -N( (CH2) -SO-R, -S0 2 -R, -Si-R, -SiO-R, -NH- (CH 2 ) n -, -N ((CH 2 )
0-(CH2)n-R6, -S- (CH2)n-R6' -Si- (CH2)n-R6; donde R es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: - CO-Z-alquilo C1-C15, -Z-CO-alquilo C1-C15, -H, -ter-butilo, - iso-propilo, -alquilo C1-C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, - 0-R7,-CN, -S-R7, -S-CF3 y fenilo sustituido a su vez con -H, - alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde X es O, N o S; donde n= 0-14; donde m= 0-14; donde 0= 1-14; donde K, Z, P, G, I, Y, J y W son independientemente: O, N, S02, SO, S, C o Si; 0- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 '-Si- (CH 2 ) n -R 6 ; where R is a C 1 -C 15 alkyl group, a substituted C 1 -C 15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C 1 - alkyl groups C15, aryl, phenyl, heterocycle and heteroaryl are: - CO-Z-C1-C15 alkyl, -Z-CO-C1-C15 alkyl, -H, -ter-butyl, - iso-propyl, -C1-C15 alkyl, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 and phenyl substituted in turn with -H, - C1-C15 alkyl, halo of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH; where X is O, N or S; where n = 0-14; where m = 0-14; where 0 = 1-14; where K, Z, P, G, I, Y, J and W are independently: O, N, S0 2 , SO, S, C or Si;
R2 es -H, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6 y halógeno del grupo de Cl, Br, F y I; R 2 is -H, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 and halogen of the group Cl, Br, F and I ;
R3 es H, alquilo C1-C15, -NH2 , -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, - S-R6; donde heterociclo se define como un anillo monocíclico , que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo; donde heteroarilo se define como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 6 a 12 átomos de carbono; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: -H, - alquilo C1-C15, alquilo sustituido C1-C15 con R7, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO- R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, -ter-butilo, -iso-propilo y -CF3. R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , - SR 6 ; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; wherein heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, which has between 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 6 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: -H, - C1-C15 alkyl, C1-C15 substituted alkyl with R 7 , halo of the group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 , -ter-butyl, -iso-propyl and -CF 3 .
Por otro lado, un segundo grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula I, donde R es -NH- (CH2) n- , -O- ( CH2 ) n-R , -S-(CH2)n-R ; donde R es un grupo fenilo sustituido, donde las sustituciones del grupo fenilo son independientemente: —Z—CO—alquilo Ci— C15, -CO-Z-alquilo C1-C15, -H, -ter-butilo, -iso-propilo, -alquilo C1-C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, - NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3y fenilo sustituido con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, - OCO-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde n= 0-2; donde z es independientemente: O, N, S02, SO, S, C o Si; On the other hand, a second preferred group of the compounds of the present invention includes compounds possessing formula I, wherein R is -NH- (CH 2 ) n-, -O- (CH 2 ) n -R, -S- (CH 2 ) n -R; where R is a substituted phenyl group, where the substitutions of the phenyl group are independently: -Z-CO-Ci - C15 alkyl, -CO-Z-C1-C15 alkyl, -H, -ter-butyl, -iso-propyl, -C1-C15 alkyl, -CF 3 , halogen of the group Cl, Br, F and I, -NH 2 , -N0 2 , - NH-R 7 , -N (R 7 ) 2, -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 and phenyl substituted with -H, -C1-C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , - OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH; where n = 0-2; where z is independently: O, N, S0 2 , SO, S, C or Si;
R es H; R3 es H y alquilo C1-C15, donde R4 y R5 son H, un grupo alquilo C1-C15. Por otro lado, un tercer grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula I, donde R es -NH- (CH2) n- , -0-(CH2)n- , -S-(CH2)n-R ; donde R6 es un grupo alquilo C1-C15 o un grupo fenilo sustituido, donde las sustituciones del grupo fenilo son independientemente: -H, -alquilo C1-C15 y halógeno del grupo de Cl, Br, F y I ; donde n= 0-2; R is H; R 3 is H and C1-C15 alkyl, where R 4 and R 5 are H, a C1-C15 alkyl group. On the other hand, a third preferred group of the compounds of the present invention includes compounds possessing formula I, where R is -NH- (CH 2 ) n -, -0- (CH 2 ) n -, -S- ( CH 2 ) n -R; wherein R 6 is a C 1 -C 15 alkyl group or a substituted phenyl group, where the substitutions of the phenyl group are independently: -H, -C 1 -C 15 alkyl and halogen of the group of Cl, Br, F and I; where n = 0-2;
R2 es -H, -NH-R6, -N- (R6) 2, -O-R6, -S-R6; R 2 is -H, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 ;
R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15; donde las sustituciones R6 del grupo fenilo están en posiciones orto y para. R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where the R 6 substitutions of the phenyl group are in ortho and para positions.
Por otro lado, un cuarto grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula I, donde
Figure imgf000031_0001
On the other hand, a fourth preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
Figure imgf000031_0001
donde X es O, N o S; Rz es -H; where X is O, N or S; R z is -H;
R3 es H, alquilo Ci-Ci5; donde R4 y R5 son H, un grupo alquilo C1-C15. R 3 is H, Ci-Ci 5 alkyl; where R 4 and R 5 are H, a C1-C15 alkyl group.
Por otro lado, un quinto grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula I, donde On the other hand, a fifth preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
Figure imgf000031_0002
donde n= 0-8; donde w es independientemente: O, N, SO2, SO, S, C o Si; donde y, z y j son C o N; Rz es -H;
Figure imgf000031_0002
where n = 0-8; where w is independently: O, N, SO 2 , SO, S, C or Si; where y, z and j are C or N; R z is -H;
R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: -H, - alquilo C1-C15, alquilo sustituido C1-C15 con R7, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO- R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, -ter-butilo, -iso-propilo y -CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH. R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where R 8, R 9, R 10 and R 11 are independently -H, - C1-C15 alkyl, substituted C1-C15 with R 7, halogen group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S -CF 3 , -ter-butyl, -iso-propyl and -CF 3 ; where R 7 is a group -H, C 1 -C 15 alkyl, -OH.
Por otro lado, un sexto grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula donde On the other hand, a sixth preferred group of the compounds of the present invention includes compounds possessing the formula where
Figure imgf000032_0001
Figure imgf000032_0001
R es donde n= 0-8; donde m= 0-6; donde o= 1-6; donde Z, J son independientemente: O, N, SO2, SO, S, C o Si; donde Y es C o N; R2 es -H; R is where n = 0-8; where m = 0-6; where o = 1-6; where Z, J are independently: O, N, SO 2 , SO, S, C or Si; where Y is C or N; R 2 is -H;
R3 es H, alquilo C1-C15; donde R4 y R5 son -H, un grupo alquilo C1-C15; R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are -H, a C 1 -C 15 alkyl group;
Por otro lado, un séptimo grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula I, donde On the other hand, a seventh preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
Figure imgf000033_0001
donde n= 0-8; donde Z es independientemente: O, N, SO2, SO, S, C o Si; donde Y es C o N; R2 es -H;
Figure imgf000033_0001
where n = 0-8; where Z is independently: O, N, SO 2 , SO, S, C or Si; where Y is C or N; R 2 is -H;
R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15. R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group.
Por otro lado, un octavo grupo preferido de los compuestos de la presente invención incluye compuestos que poseen la formula I, donde On the other hand, an eighth preferred group of the compounds of the present invention includes compounds possessing formula I, wherein
Figure imgf000034_0001
donde n= 0-8; donde K, Z son independientemente: O, N, SO2, SO, S, C o Si; donde G, I, Y, J y W son independientemente: N o C; R es -H;
Figure imgf000034_0001
where n = 0-8; where K, Z are independently: O, N, SO 2, SO, S, C or Si; where G, I, Y, J and W are independently: N or C; R is -H;
R3 es -H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R9, R10 y R11 corresponden independientemente a: -H, - alquilo C1-C15, alquilo sustituido C1-C15 con R7, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO- R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, -ter-butilo, -iso-propilo y -CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH. El término halógeno' como se usa en este documento se refiere a flúor, cloro, bromo o yodo, salvo que se indique de otro modo. R 3 is -H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where R 9, R 10 and R 11 are independently -H, - C1-C15 alkyl, substituted alkyl C 1-C15 with R 7, halogen group Cl, Br, F and I, -NH 2, - N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO- R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 , -ter-butyl, -iso-propyl and -CF 3 ; where R 7 is a group -H, C 1 -C 15 alkyl, -OH. The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, unless otherwise indicated.
El término Alquilo' como se usa en este documento se refiere a un residuo de hidrocarburo lineal, cíclico o ramificado, de preferencia un grupo alquilo de entre 1 a 15 átomos de carbono, salvo que se indique de otro modo. El término >cicloalquilo' como se usa en este documento se refiere a un alquilo cíclico, por e . , ciclopropilo, salvo que se indique de otro modo. El término ^rilo' como se usa en este documento se refiere a un grupo aromático monocíclico o bicíclico, en el cual cada anillo del sistema de anillos individual o fusionados contiene 6-12, preferentemente 6-10 átomos cíclicos [sic], por e . , incluye fenilo, naftilo, bifenilo e indenilo, pero no siempre se limita a éstos. The term "Alkyl" as used herein refers to a linear, cyclic or branched hydrocarbon residue, preferably an alkyl group of 1 to 15 carbon atoms, unless otherwise indicated. The term > cycloalkyl 'as used herein refers to a cyclic alkyl, for e. , cyclopropyl, unless otherwise indicated. The term "rile" as used herein refers to a monocyclic or bicyclic aromatic group, in which each ring of the individual or fused ring system contains 6-12, preferably 6-10 cyclic atoms [sic], by e . , includes phenyl, naphthyl, biphenyl and indenyl, but is not always limited to these.
El término >heterocicloalquilo' o "hetertociclo" como se usa en este documento se refiere a un alquilo cíclico, por ej . , alquilo monocíclico o bicíclico, que contiene uno o más heteroátomos , con preferencia uno a cuatro heteroátomos , seleccionados de O, N y S, salvo que se indique de otro modo. Algunos ejemplos de monoheterocicloalquilo incluyen piperidinilo, morfolinilo, tiamorfolinilo, pirrolidinilo, imidazolidinilo, tetrahidrofuranilo, piperazinilo y grupos similares de los anteriores, aunque no se limitan a éstos. Donde "heterociclo", dentro de los >heterocicloalquilo' , se define como un anillo monocíclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo. El término heteroarilo' como se usa en este documento se refiere a un grupo aromático, por e . , grupo monociclico o biciclico, que contiene uno a cuatro heteroátomos seleccionados de O, N y S, y uno o más de carbonos como miembros del anillo están sustituidos con C=0, salvo que se indique de otro modo. Algunos ejemplos de heteroarilo monociclico incluyen tiazolilo, oxazolilo, tiofenilo, furanilo, pirrolilo, imidazolilo, isooxazolilo, pirazolilo, triazolilo, tiadiazolilo, tetrazolilo, oxadiazolilo, piridinilo, piridazinilo, pirimidinilo, pirazinilo y grupos similares de los anteriores, aunque no se limitan a éstos. Algunos ejemplos de heteroarilo biciclico incluyen indolilo, benzotiofenilo, benzofuranilo, benzimidazolilo, benzoxazolilo, bencisoxazolilo, benztiazolilo, benzotiadiazolilo, benztriazolilo, quinolinilo, isoquinolinilo, furinilo, furopiridinilo, oxocromeno, dioxoisoindolina y grupos similares de los anteriores, aunque no se limitan a éstos. Donde en una definición especifica, "heteroarilo" se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S. The term > heterocycloalkyl 'or "heterocycle" as used herein refers to a cyclic alkyl, eg. , monocyclic or bicyclic alkyl, containing one or more heteroatoms, preferably one to four heteroatoms, selected from O, N and S, unless otherwise indicated. Some examples of monoheterocycloalkyl include piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and similar groups of the foregoing, although not limited thereto. Where "heterocycle", within the > heterocycloalkyl ', is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring. The term "heteroaryl" as used herein refers to an aromatic group, for e. , monocyclic or bicyclic group, containing one to four heteroatoms selected from O, N and S, and one or more carbons as ring members are substituted with C = 0, unless otherwise indicated. Some examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups thereof, although these are not limited thereto, . Some examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, bencisoxazolyl, benzthiazolyl, benzothiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, furyl, furopyridinyl, oxyindole, similar to these, although they are similar to these. Where in a specific definition, "heteroaryl" is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, which has between 1 to 4 heteroatoms selected from N, O, and S.
Los compuestos de la presente invención también pueden formar una sal aceptable desde el punto de vista farmacéutico. Dicha sal puede ser una sal de adición con ácido no tóxica aceptable desde el punto de vista farmacéutico que contiene anión, aunque no se limitan a éstos. Por ejemplo, la sal puede incluir sales de adición con ácidos formadas por ácidos inorgánicos tales como ácido clorhídrico, ácido sulfúrico, ácido nítrico, ácido fosfórico, ácido bromhídrico, ácido hidriódico, y otros; ácidos carbónicos orgánicos tales como ácido tartárico, ácido fórmico, ácido cítrico, ácido acético, ácido tricloroacético, ácido trifluoroacético, ácido glucónico, ácido benzoico, ácido láctico, ácido fumárico, ácido maleico, y otros; y ácidos sulfónicos tales como ácido metansulfónico, ácido bencensulfónico, ácido p- toluensulfónico, ácido naftalensulfónico, y otros. En forma adicional, el compuesto de la presente invención puede tener un centro de carbono asimétrico, y de este modo puede estar presente en la forma de isómero R o S, compuestos racémicos, mezcla diasteromérica, o diasterómero individual, dichos isómeros enteros y mezclas se incluyen dentro del alcance de la presente invención The compounds of the present invention can also form a pharmaceutically acceptable salt. Said salt may be an pharmaceutically acceptable non-toxic acid addition salt containing anion, although not limited thereto. For example, the salt may include addition salts with acids formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydric acid, and others; organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and others; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and others. Additionally, the compound of the present invention may have an asymmetric carbon center, and thus may be present in the form of an R or S isomer, racemic compounds, diasteromeric mixture, or individual diasteromer, said whole isomers and mixtures. included within the scope of the present invention
Además, los solvatos e hidratos del compuesto de la fórmula (I) se abarcan dentro del alcance de la presente invención . Los compuestos anteriores de la presente invención pueden prepararse mediante métodos que son conocidos en el arte o de acuerdo con los siguientes ejemplos de trabajo. Los compuestos a continuación, son especialmente representativos de los compuestos de la presente invención. In addition, the solvates and hydrates of the compound of the formula (I) are encompassed within the scope of the present invention. The above compounds of the present invention can be prepared by methods that are known in the art or in accordance with the following working examples. The compounds below are especially representative of the compounds of the present invention.
6-etil-2, 4-dimetilpirimido [4, 5-c] isoquinolin-1 , 3,7,10 (2H, 4JJ) - tetraona 6-etil-2, 4-dimetil-8- ( feniltio ) pirimido [4, 5-c] i soquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4JJ) - tetraone 6-ethyl-2,4-dimethyl-8- (phenylthio) pyrimido [4 , 5-c] and soquinolin- 1,3,7,10 (2H, 4JJ) -tetraone
6-etil-2, 4-dimetil-8- (o-toliltio) pirimido [4, 5-c] i soquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 6-ethyl-2, 4-dimethyl-8- (o-tolylthio) pyrimido [4,5-c] and soquinolin- 1,3,7,10 (2H, 4JJ) -tetraone
6-etil-8- ( (2-metoxifenil) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraona 6-ethyl-8- ((2-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
6-etil-8- ( (2-fluorofenil) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraona 6-ethyl-8- ((2-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 2-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraona 8- ( ( 2-bromofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((2-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 8- ((2-bromophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
6-etil-2, 4-dimetil-8- (m-toliltio) pirimido [4, 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 6-ethyl-2, 4-dimethyl-8- (m-tolylthio) pyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone
6-etil-8- ( ( 3-metoxifenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 6-etil-8- ( ( 3-fluorofenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 6-ethyl-8- ((3-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 6-ethyl-8- ( (3-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 3-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((3-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 3-bromofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((3-bromophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
6-etil-2, 4-dimetil-8- (p-toliltio) pirimido [4, 5-c] isoquinolin- 1,3,7,10 (2fí, 4fí) -tetraona 6-ethyl-2, 4-dimethyl-8- (p-tolylthio) pyrimido [4,5-c] isoquinolin- 1,3,7,10 (2fí, 4fí) -tetraone
6-etil-8- ( ( 4-metoxifenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 6-etil-8- ( ( 4-fluorofenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 6-ethyl-8- ((4-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 6-ethyl-8- ((4-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 4-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((4-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 4-bromofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 6-etil-8- ( ( 4-hidroxifenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((4-bromophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 6-ethyl-8- ( (4-hydroxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
6-etil-2, 4-dimetil-8- ( (4-nitrofenil)tio) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 6-ethyl-2, 4-dimethyl-8- ((4-nitrophenyl) thio) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 4-aminofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((4-aminophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( (2, 6-dimetoxifenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((2,6-dimethoxyphenyl) thio) -6-ethyl-2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 5-bromo-2-metoxifenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ( (3, 5-diclorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((5-Bromo-2-methoxyphenyl) thio) -6-ethyl-2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 8- ((3, 5-dichlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- (benciltio) -6-etil-2, 4-dimetilpirimido [4, 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona 8- (benzylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraone
8- ( ( 4-clorobencil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-etil-2, 4-dimetil-8- ( fenetiltio ) pirimido [4, 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 8- ((4-Chlorobenzyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone 6-ethyl-2, 4 -dimethyl-8- (phenethylthio) pyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone
8-(benzo[d]oxazol-2-iltio)-6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- (benzo [d] oxazol-2-ylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 2-bromo-4-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((2-Bromo-4-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
8- ( ( 4-aminofenil ) amino) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ((4-aminophenyl) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone
6-etil-2, 4-dimetil-8- ( feni lamino ) pirimido [4, 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 6-ethyl-2, 4-dimethyl-8- (phenylamino) pyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone
6-etil-8- ( ( 4-fluorofenil ) amino) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraona 8- ( ( 4-clorofenil ) amino) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona 8- ( ( 4-bromofenil ) amino) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4JJ) -tetraona metil 4- ( ( 6-etil-2, 4-dimetil-l, 3,7, 10-tetraoxo-l, 2, 3,4,7,10- hexahidropirimido [4, 5-c] isoquinolin-8-il) amino) benzoato . 6-ethyl-8- ((4-fluorophenyl) amino) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 8- ((4-chlorophenyl) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 8- ((4-bromophenyl) ) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone methyl 4- ((6-ethyl-2, 4-dimethyl -l, 3,7, 10-tetraoxo-l, 2, 3,4,7,10-hexahydropyrimido [4,5-c] isoquinolin-8-yl) amino) benzoate.
La dosis eficaz de los derivados de pirimido-isoquinolin- quinonas representados por la fórmula I, sus hidratos, sus solvatos o sus sales aceptadas para uso farmacéutico, puede determinarse considerando los compuestos específicos que se utilicen, el método de administración, el individuo elegido, la enfermedad elegida, etc., para llevar a efecto el The effective dose of the pyrimido-isoquinolinquinone derivatives represented by the formula I, its hydrates, its solvates or its salts accepted for pharmaceutical use, can be determined considering the specific compounds used, the method of administration, the chosen individual, the chosen disease, etc., to carry out the
tratamiento, no obstante 5-40 mg/kg de peso corporal por día es el rango de dosis preferida del compuesto derivado treatment, however 5-40 mg / kg body weight per day is the preferred dose range of the derived compound
pirimido-isoquinolin-quinonas representado por la fórmula I, teniendo en cuenta que los compuestos de la presente invención poseen un alto porcentaje de unión a albúmina. La dosis diaria puede ser administrada una vez al día (en un tiempo) o varias veces al día cuando se divide apropiadamente dentro de una dosis diaria eficaz. De acuerdo con la formulación, es posible la administración oral, la administración parenteral (inyección) o la administración local. La composición farmacéutica de la presente invención puede ser formulada para administración oral como tabletas, polvos, jarabes secos, tabletas masticables, gránulos, cápsulas, cápsulas suaves, pildoras, bebidas, sublinguales, etc. La composición de la invención formulada como tabletas puede administrarse a un individuo por cualquier método o vía que entregue la dosis eficaz de la tableta con la biodisponibilidad, la cual puede ser la vía oral. También el método o la vía de administración pueden ser determinados de acuerdo con las características, etapas de la enfermedad objetivo u otros estados. Cuando la composición de la invención se forma como tabletas, estas pueden incluir además excipientes aceptados para uso pyrimido-isoquinolin-quinones represented by the formula I, taking into account that the compounds of the present invention possess a high percentage of albumin binding. The daily dose can be administered once a day (at a time) or several times a day when properly divided into an effective daily dose. According to the formulation, oral administration, parenteral administration is possible (injection) or local administration. The pharmaceutical composition of the present invention can be formulated for oral administration as tablets, powders, dried syrups, chewable tablets, granules, capsules, soft capsules, pills, beverages, sublinguals, etc. The composition of the invention formulated as tablets may be administered to an individual by any method or route that delivers the effective dose of the tablet with bioavailability, which may be the oral route. Also the method or route of administration can be determined according to the characteristics, stages of the target disease or other conditions. When the composition of the invention is formed as tablets, they may also include excipients accepted for use.
farmacéutico. El contenido y las características del pharmacist. The content and characteristics of the
excipiente pueden ser determinados por las propiedades de solubilidad y químicas de la tableta elegida, la vía de excipient can be determined by the solubility and chemical properties of the chosen tablet, the route of
administración y la práctica farmacéutica normal. Administration and normal pharmaceutical practice.
Las composiciones farmacéuticas pueden prepararse combinando una cantidad terapéuticamente efectiva de por lo menos un compuesto de acuerdo con la presente invención, o una sal de adición de ácido farmacéuticamente aceptable del mismo, como un ingrediente activo, con excipientes farmacéuticos convencionales y/o aditivos, y mediante la preparación de formas de dosis de unidad adecuadas para uso como antibiótico. En la presente invención, los aditivos aceptables desde el punto de vista farmacéutico pueden incluir un diluyente, un aglutinante, un desintegrante, y similares. The pharmaceutical compositions can be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional pharmaceutical excipients and / or additives, and by preparing unit dosage forms suitable for use as an antibiotic. In the present invention, pharmaceutically acceptable additives may include a diluent, a binder, a disintegrant, and the like.
Algunos ejemplos del diluyente pueden incluir celulosa microcristalina, lactosa, manitol, fosfato de calcio, y similares; algunos ejemplos del aglutinante pueden incluir povidona, hidroxipropil celulosa (HPC) , hidroxipropil metil celulosa (HPMC) , alcohol polivinilico (PVA) , carboximetil celulosa de sodio, y similares; y algunos ejemplos del desintegrante pueden incluir crospovidona, croscarmelosa de sodio, almidón glicolato de sodio, y similares. Otros, aditivos o vehículos para formulaciones orales comprenden celulosa, silicato de calcio, almidón de maíz, sacarosa, dextrosa, ácido esteárico, estearato de magnesio, estearato de calcio, gelatina, talco, tensioactivos , agentes de suspensión, agentes emulsionantes y otros. Some examples of the diluent may include microcrystalline cellulose, lactose, mannitol, calcium phosphate, and the like; Some examples of the binder may include povidone, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose, and the like; and some examples of the disintegrant may include crospovidone, croscarmellose sodium, sodium starch glycolate, and the like. Others, additives or vehicles for oral formulations include cellulose, calcium silicate, corn starch, sucrose, dextrose, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents and others.
El diluyente puede usarse en una cantidad que varía desde 20 hasta 95% en peso, el aglutinante puede usarse en una cantidad que varía desde 1 hasta 10% en peso, y el desintegrante puede usarse en una cantidad que varía desde 1 hasta 30% en peso, en base al peso total de la composición. Para las formulaciones parenterales tales como administración intramuscular, intravenosa, o subcutánea, los aditivos o vehículos tales como agua, solución salina, solución de glucosa, análogos a la solución de glucosa, alcoholes, glicoles, éteres (por e . , polietilenglicol 400), aceites, ácidos grasos, ésteres del ácido graso, glicéridos, tensioactivos , agentes de suspensión, agentes emulsionantes, y otros pueden usarse, de preferencia, las soluciones salinas fisiológicas como un portador principal. The diluent can be used in an amount ranging from 20 to 95% by weight, the binder can be used in an amount ranging from 1 to 10% by weight, and the disintegrant can be used in an amount ranging from 1 to 30% in weight. weight, based on the total weight of the composition. For parenteral formulations such as intramuscular, intravenous, or subcutaneous administration, additives or vehicles such as water, saline solution, glucose solution, glucose solution analogues, alcohols, glycols, ethers (eg, polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents, and others, preferably, physiological saline solutions can be used as a major carrier.
El pH de dichas soluciones debería en forma preferida mantenerse entre 6,5 y 7,2 con un sistema de amortiguación adecuada. Las formulaciones puede también contener conservantes, estabilizantes y surfactantes convencionales farmacéuticamente aceptables. The pH of said solutions should preferably be maintained between 6.5 and 7.2 with a suitable buffer system. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
Los conservantes preferidos que pueden utilizarse en las composiciones farmacéuticas de la presente invención incluyen, sin limitarse a ello, alcohol bencílico, propilparabeno, metilparabeno, cloruro de benzalconio, clorobutanol , timerosal, acetato fenilmercúrico y nitrato fenilmecúrico . Un surfactante preferido es por ejemplo Tween 80, sin limitarse a este únicamente. Del mismo modo, pueden utilizarse diversos vehículos preferidos en las preparaciones de la presente invención. Estos vehículos incluyen, sin limitarse a ello, propilenglicol , soluciones de hidroxido de sodio, alcohol polivinilo, povidona, celulosa de metilo hidroxipropilo, poloxámeros, celulosa carboximetilo, celulosa hidroxietilo y agua purificada. Preferred preservatives that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmecuric nitrate. A preferred surfactant is, for example, Tween 80, without being limited thereto only. Similarly, various preferred vehicles may be used in the preparations herein. invention. These vehicles include, but are not limited to, propylene glycol, sodium hydroxide solutions, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Los ajustadores de tonicidad pueden agregarse según sea necesario o conveniente. Ellos incluyen, sin limitarse a ello, sales, particularmente cloruro de sodio, cloruro de potasio, manitol y glicerina, o cualquier otro ajustador de tonicidad adecuado y aceptable. Tonicity adjusters can be added as necessary or convenient. They include, without limitation, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable and acceptable tonicity adjuster.
Pueden utilizarse varios amortiguantes y medios para ajusfar el pH en tanto que la preparación resultante sea oftálmicamente aceptable. De acuerdo con ello, los amortiguantes incluyen amortiguantes de acetato, amortiguantes de citrato, amortiguantes de fosfato y amortiguantes de borato. Los ácidos o bases pueden utilizarse para ajusfar el pH de estas formulaciones según sea necesario. Various buffers and means can be used to adjust the pH as long as the resulting preparation is ophthalmically acceptable. Accordingly, the buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. The acids or bases can be used to adjust the pH of these formulations as necessary.
En una forma similar, un antioxidante aceptable para uso en la presente invención incluye, sin limitarse a ello, metabisulfito de sodio, tiosulfato de sodio, acetilcisteína, hidroxianisol butilado y hidroxitolueno butilado. Otros componentes excipientes tanto en solución liquida como composición oral, que pueden incluirse en las preparaciones son los agentes quelantes. Dentro de los agentes quelantes a utilizar se pueden mencionar el etilendiaminotetraacetato de calcio y disodio (CaNa2EDTA) , el ácido trietilentetraminohexaacético (TTHA) , el ácido dihidroxietiletilendiaminodiacético, el ácido hidroxietiletilendiaminotriacético (HEDTA) , el oxalato y sus derivados, el ( 1 , 2-bis (difenilfosfino ) etileno (DPPE) el dimercaprol (BAL) , el dietilentriaminopentaacético (DTPA) , de preferencia se utiliza el ácido etilendiaminotetraacético (EDTA) , aunque pueden también utilizarse otros agentes quelantes en lugar del mismo o con untamente con dicho agente. El EDTA posee en esta invensión una función doble, por un lado es un agente quelante que tiende a atrapar partículas metálicas. Por otro lado, el EDTA aunque no ha sido reconocido como un agente antimicrobiano, en general, es considerado como un "potenciador" de la actividad de otros agentes antimicrobianos (Brown y Richards 1965) . Como tal, la literatura ha escrito sobre éste un efecto sinérgico o de refuerzo común a la acción con conservantes, antibióticos y tensioactivos catiónicos, por ejemplo, compuestos de amonio cuaternario (Weiser et al. 1969; Sheikh y Parker 1972; Hart 1984; Vaara 1992) . Mecanisticamente, uno de los modos reconocidos de acción de EDTA es la interrupción de la estructura de lipopolisacárido en la membrana externa de las bacterias Gram- negativas. A través de esto la disrupción de la membrana se vuelve más permeable a otros agentes, por lo tanto, la acción potenciadora . Sumado a esto, si se toma la acción del EDTA en combinación con una lisozima para degradar la capa de peptidoglicano puede resultar en la producción de esferoplastos, en la que la pared celular es totalmente despojada (MacGregor y Elliker 1958; Haque y Russell 1974a, b) . In a similar manner, an antioxidant acceptable for use in the present invention includes, without limitation, sodium metabisulphite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Other excipient components in both liquid solution and oral composition, which can be included in the preparations are chelating agents. Among the chelating agents to be used can be mentioned ethylenediaminetetraacetate calcium and disodium (CaNa2EDTA), triethylenetetraminehexaacetic acid (TTHA), dihydroxyethylenediamine diacetic acid (hydroxyethylenediaminetriacetic acid (HEDTA), oxalate 1, its derivatives, oxalato (2) bis (diphenylphosphino) ethylene (DPPE) dimercaprol (BAL), diethylenetriaminepentaacetic acid (DTPA), preferably ethylenediaminetetraacetic acid (EDTA) is used, although other chelating agents may also be used instead or with said agent alone. EDTA has a double function in this invention, on the one hand it is a chelating agent that tends to trap metal particles.On the other hand, EDTA has not been recognized as an antimicrobial agent, in general, it is considered as an "enhancer" of the activity of other antimicrobial agents (Brown and Richards 1965) As such, the literature has written about it an effect synergistic or common reinforcement to action with preservatives, antibiotics and cationic surfactants, for example, quaternary ammonium compounds (Weiser et al. 1969; Sheikh and Parker 1972; Hart 1984; Vaara 1992). Mechanically, one of the recognized modes of action of EDTA is the disruption of the lipopolysaccharide structure in the outer membrane of Gram-negative bacteria. Through this the disruption of the membrane becomes more permeable to other agents, therefore, the potentiating action. Added to this, if the action of EDTA is taken in combination with a lysozyme to degrade the peptidoglycan layer it can result in the production of spheroplasts, in which the cell wall is completely stripped (MacGregor and Elliker 1958; Haque and Russell 1974a, b).
Una de las pruebas realizadas y que abarca el presente desarrollo es la combinación de los agentes descritos de formula I con EDTA, donde se amplia el campo de acción de éste antibiótico a bacterias Gram (-) . One of the tests carried out and covering the present development is the combination of the agents described in formula I with EDTA, where the field of action of this antibiotic to Gram (-) bacteria is extended.
Lo mencionado anteriormente está demostrado en la tabla IV en las pruebas experimentales. The aforementioned is shown in Table IV in the experimental tests.
Los ingredientes son generalmente utilizados en las cantidades siguientes para las diferentes composiciones farmacéuticas, sin ser restrictivas a las mismas, pudiéndose utilizar el mismo principio activo en otras composiciones: COMPRIMIDOS The ingredients are generally used in the following amounts for the different pharmaceutical compositions, without being restrictive thereto, the same active ingredient can be used in other compositions: TABLETS
Materias primas Cantidad (%peso/peso)Raw materials Quantity (% weight / weight)
Ingrediente activo granulado 80, 0-95, 0 Granulated active ingredient 80, 0-95, 0
Dextrosa 0-1, 0  Dextrose 0-1, 0
Celulosa microcristalina (Avicel pH 10.1) 0-3, 0  Microcrystalline cellulose (Avicel pH 10.1) 0-3, 0
Almidón 0-2, 0  Starch 0-2, 0
Talco 0-1, 0  Talc 0-1, 0
Materias primas Cantidad (%peso/peso) Ingrediente Activo 95, 0-99, 0 Raw materials Quantity (% weight / weight) Active Ingredient 95, 0-99, 0
Lactosa c . s . p . Lactose c. s. p.
Estearato de magnesio 5-1  Magnesium Stearate 5-1
EMULSIONES (o/w) EMULSIONS (o / w)
Materias Primas Cantidad (% peso/peso)Raw Materials Quantity (% weight / weight)
Ingrediente Activo 1,0-5, 0 Active Ingredient 1.0-5, 0
Acido esteárico 7,0-9, 0  Stearic acid 7.0-9.0
Petrolato blanco 1,0-3,0  White Petrolatum 1.0-3.0
Aceite mineral 1,0-3,0  Mineral oil 1.0-3.0
Trietanolamina c . s .p  Triethanolamine c. s .p
Propilenglicol 4,0-6, 0  Propylene Glycol 4.0-6.0
Metilparabeno 0, 1-0,3  Methylparaben 0, 1-0.3
Propilparabeno 0, 1-0,3  Propylparaben 0, 1-0.3
Agua Destilada Estéril c . s .p  Sterile Distilled Water c. s .p
POMADA BLANCA WHITE POMADA
Materias Primas Cantidad (% peso/peso) Ingrediente activo 8,0 - 12,0  Raw Materials Quantity (% weight / weight) Active ingredient 8.0 - 12.0
Aceite mineral 38,0 - 42,0 Mineral oil 38.0 - 42.0
Petrolato blanco 38,0 - 42,0 White Petrolatum 38.0 - 42.0
INYECTABLE INJECTABLE
Materias Primas Cantidad (% peso/peso) Ingrediente activo 1,0 - 10, o  Raw Materials Quantity (% weight / weight) Active ingredient 1.0 - 10, or
Cloruro de Sodio 0, 9 Sodium Chloride 0, 9
Acido Láctico 0, 1-5, 0 Lactic Acid 0, 1-5, 0
Edetato Disódico 0, 1-5, 0 Disodium Edetate 0, 1-5, 0
Agua para Inyectable c . s . p . Esta invención se ilustra además por los siguientes ejemplos no limitativos. Water for injection c. s. p. This invention is further illustrated by the following non-limiting examples.
Ejemplo 1 Example 1
Procedimiento general de obtención de 6-etil-2,4- dimetilpirimido [ , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (compuesto intermediario 1) . General procedure for obtaining 6-ethyl-2,4-dimethylpyrimido [, 5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (intermediate compound 1).
Figure imgf000051_0001
Figure imgf000051_0001
Compuesto Intermediario 1  Intermediate Compound 1
Una solución de 1- (2, 5-dihidroxifenil ) -propan-l-ona (166,6 mg, 1 mmol), 6-amino-l , 3-dimetilpirimidina-2 , 4 ( 1H, 3H) -diona (201,7 mg, 1,3 mmol), MgSÜ4 (300, 0 mg, 3 mmol), Ag2Ü (927, 0 mg, 3 mmol) en CH2CI2 (20 mi) se mantiene en agitación durante 2 horas. El avance de la reacción se sigue por medio de cromatografía de capa fina a 30, 60, 90 y 120 minutos. El crudo de reacción se filtra al vacío con papel filtro y celite en embudo Buchner utilizando CH2CI2 para arrastrar el producto. La solución obtenida de la filtración se evapora hasta sequedad . A solution of 1- (2, 5-dihydroxyphenyl) -propan-l-one (166.6 mg, 1 mmol), 6-amino-l, 3-dimethylpyrimidine-2, 4 (1H, 3H) -dione (201 , 7 mg, 1.3 mmol), MgSO 4 (300.0 mg, 3 mmol), Ag 2 Ü (927.0 mg, 3 mmol) in CH 2 CI 2 (20 mL) is kept under stirring for 2 hours . The progress of the reaction is followed by thin layer chromatography at 30, 60, 90 and 120 minutes. The reaction crude is filtered under vacuum with Buchner funnel and celite paper using CH 2 CI 2 to drag the product. The solution obtained from the filtration is evaporated to dryness.
El sólido resultante se purifica con 30 g de Silica gel (0,040-0,063 mm) utilizando como fase móvil diclorometano : acetato de étilo = 9:1. Se obtiene un sólido de color amarillo, 244,7 mg, 0,65 mmol, 80% de rendimiento. The resulting solid is purified with 30 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: ethyl acetate = 9: 1. A yellow solid is obtained, 244.7 mg, 0.65 mmol, 80% yield.
Punto fusión 167,6 - 167, 9°C. HRMS (M+) : m/z calculado C15H13N3O4 = 299, 09061; encontrado = 299, 09070. IR (KBr) : 1667,28 cnf1 C=0 (quinona); 1720.35 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.41 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.70 (dd, 3J=7.2 Hz, 2H, 6- CH2CH3 ) , 3.47 (s, 3H, 4-NCH3) , 3.77 (s, 3H, 2- NCH3) , 6.88 (d, 3J=10.3 Hz, 1H, 8-H) , 7.18 (d, 3J=10.3 Hz, 1H, 9-H) . 13C RMN (CDCI3, 100 MHz) : δ 12.0 (6-CH2CH3), 29.0 (4- NCH3) , 30.1 (2-NCH3 ) , 31.5 (6- CH2CH3 ) , 105.3 (10b), 121.2 (6a),Melting point 167.6 - 167.9 ° C. HRMS (M +): m / z calculated C 15 H 13 N 3 O 4 = 299, 09061; found = 299, 09070. IR (KBr): 1667.28 cnf 1 C = 0 (quinone); 1720.35 cnf 1 C = 0 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.41 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.70 (dd, 3 J = 7.2 Hz, 2H, 6- CH2CH 3 ), 3.47 (s, 3H, 4-NCH 3 ), 3.77 (s, 3H, 2- NCH 3 ), 6.88 (d, 3 J = 10.3 Hz, 1H, 8-H), 7.18 (d, 3 J = 10.3 Hz, 1H, 9-H). 13 C NMR (CDCI 3 , 100 MHz): δ 12.0 (6-CH 2 CH 3 ), 29.0 (4- NCH 3 ), 30.1 (2-NCH 3 ), 31.5 (6- CH2CH 3 ), 105.3 (10b) , 121.2 (6a),
138.6 (9-C), 138.7 (8), 146.9 (10a), 150.9 (3), 152.6 (1),138.6 (9-C), 138.7 (8), 146.9 (10a), 150.9 (3), 152.6 (1),
158.7 (4a), 170.3 (6), 183.7 (7), 185.2 (10) . Ejemplo 2 158.7 (4a), 170.3 (6), 183.7 (7), 185.2 (10). Example 2
Obtención de 6-etil-2 , 4-dimetil-8- (feniltio) pirimido [4 , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (2) .
Figure imgf000053_0001
Obtaining 6-ethyl-2,4-dimethyl-8- (phenylthio) pyrimido [4, 5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (2).
Figure imgf000053_0001
2  2
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (452, 02 mg, 2,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de tiofenol (83,20 mg, 1,0 mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 50 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : éter de petróleo: acetato de étilo = 9:8:1. Se obtiene un sólido de color naranjo, 196 mg, 0,48 mmol, con 67% rendimiento. Punto de fusión 179.4 - 180.0 °C. HRMS (M+) : m/z calculado C21H17N3O4 S [M+] = 407.09398; encontrado = 407.09400. IR (KBr) : 1660.18, 1688.50 cnf1 C=0 (quinona) ; 1723.89 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.38 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.42 (c, 3J=7.3 Hz, 2H, 6-CH2CH3) , 3.45 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.18 (s, 1H, 9-H) , 7.53 (m, 5H, 8-SC6H5) . 13C RMN (CDCI3, 100 MHz) : δ 12.1 (6-CH2CH3), 29.6 (4-NCH3), 30.1 (2- NCH3) , 31.9 (6-CH2CH3), 105.8 (10a), 121.0 (6a), 127.6 (1'), 128.3 (9), 130.9 (3' y 5' ) , 131.1 (4'), 136.1 (2' y 6' ) , 147.0 (10b), 151.5 (3), 153.1 (1), 157.1 (8), 158.8 (4a), 171.2 (6), 181.2 (10) , 181.7 (7) . A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (452.0 mg, 2.0 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of thiophene (83.20 mg,) is added dropwise 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 50 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: petroleum ether: ethyl acetate = 9: 8: 1. An orange solid, 196 mg, 0.48 mmol, is obtained in 67% yield. Melting point 179.4 - 180.0 ° C. HRMS (M +): m / z calculated C21H17N 3 O4 S [M +] = 407.09398; found = 407.09400. IR (KBr): 1660.18, 1688.50 cnf 1 C = 0 (quinone); 1723.89 cnf 1 C = 0 (uracil). ½ NMR (CDCI3, 400 MHz): δ 1.38 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.42 (c, 3 J = 7.3 Hz, 2H, 6-CH 2 CH 3 ), 3.45 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2-NCH 3 ), 6.18 (s, 1H, 9-H), 7.53 (m, 5H, 8-SC 6 H 5 ). 13 C NMR (CDCI3, 100 MHz): δ 12.1 (6-CH 2 CH 3 ), 29.6 (4-NCH 3 ), 30.1 (2- NCH3), 31.9 (6-CH 2 CH3), 105.8 (10a), 121.0 ( 6a), 127.6 (1 ' ), 128.3 (9), 130.9 (3' and 5 '), 131.1 (4'), 136.1 (2 'and 6'), 147.0 (10b), 151.5 (3), 153.1 ( 1), 157.1 (8), 158.8 (4a), 171.2 (6), 181.2 (10), 181.7 (7).
Ejemplo 3 Example 3
Obtención de 6-etil-2 , -dimetil-8- (o-toliltio) pirimido [ , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (3) . Obtaining 6-ethyl-2, -dimethyl-8- (o-tolylthio) pyrimido [, 5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (3).
Figure imgf000054_0001
Figure imgf000054_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (436, 98 mg, 2,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 2-metiltiofenol (90,67 mg, 1,0 mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 50 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : éter de petróleo: acetato de étilo =9:10:1. Se obtiene un sólido de color naranjo, 210 mg, 0,50 mmol, con 72% rendimiento. Punto de fusión 206.0 - 210.9°C. HRMS (M+) : m/z calculado C22H19N3O4 S [M+] = 421.10963; encontrado = 421.10957. IR (KBr) : 1660.18, 1688.50 cnf1 C=0 (quinona); 1730.97 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.38 (t, 3J=7.2 Hz, 3H, 6-CH2CH3) , 2.43 (s, 3H, 2'-CH3), 3.42 (c, 3J= 7.3 Hz, 2H, 6-CH2CH3) , 3.43 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.02 (s, 1H, 9-H) , 7.32 (d, 3J=7.1 Hz, 1H, 4'), 7.42 (t, 3J=8.1 Hz, 2H, 5' y 3'), 7.50 (d, 3J=7.5 Hz, 1H, 6') · 13C RMN (CDC13, 100 MHz): δ 12.1 (6- CH2CH3) , 20.5 (2'-CH3), 28.9 (4-NCH3), 30.8 (2-NCH3), 31.7 (6- CH2CH3) , 105.7 (10a), 120.9 (6a), 126.5 (1'), 127.6 (9), 128.1 (4'), 131.5 (5'), 131.8 (3'), 136.9 (6'), 142.2 (2'), 147.5 (10b), 151.2 (3), 152.9 (1), 155.6 (8), 158.6 (4a), 170.9 (6), 181.1 (7) , 181.4 (10) . A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (436, 98 mg, 2.0 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 2-methylthiophenol (90.67) is added dropwise mg, 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 50 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: petroleum ether: ethyl acetate = 9: 10: 1. An orange solid, 210 mg, 0.50 mmol, is obtained in 72% yield. Melting point 206.0 - 210.9 ° C. HRMS (M +): m / z calculated C22H1 9 N 3 O4 S [M +] = 421.10963; found = 421.10957. IR (KBr): 1660.18, 1688.50 cnf 1 C = 0 (quinone); 1730.97 cnf 1 C = 0 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.38 (t, 3 J = 7.2 Hz, 3H, 6-CH 2 CH 3 ), 2.43 (s, 3H, 2'-CH 3 ), 3.42 (c, 3 J = 7.3 Hz, 2H, 6-CH 2 CH 3 ), 3.43 (s, 3H, 4-NCH3), 3.76 (s, 3H, 2-NCH 3 ), 6.02 (s, 1H, 9-H), 7.32 ( d 3 J = 7.1 Hz, 1H, 4 '), 7.42 (t, 3 J = 8.1 Hz, 2H, 5' and 3 '), 7.50 (d, 3 J = 7.5 Hz, 1H, 6') · 13 NMR C (CDC1 3 , 100 MHz): δ 12.1 (6- CH 2 CH 3 ), 20.5 (2'-CH 3 ), 28.9 (4-NCH 3 ), 30.8 (2-NCH 3 ), 31.7 (6- CH 2 CH 3 ), 105.7 (10a), 120.9 (6a), 126.5 (1 ' ), 127.6 (9), 128.1 (4'), 131.5 (5 '), 131.8 (3'), 136.9 (6 ') , 142.2 (2 '), 147.5 (10b), 151.2 (3), 152.9 (1), 155.6 (8), 158.6 (4a), 170.9 (6), 181.1 (7), 181.4 (10).
Ejemplo 4 Example 4
Obtención de 6-etil-8- (2-metoxi eniltio) -2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (4 )
Figure imgf000056_0001
Obtaining 6-ethyl-8- (2-methoxy enylthio) -2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (4)
Figure imgf000056_0001
4  4
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (420, 99 mg, 2,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 2-metoxitiofenol (90,67 mg, 1,0 mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 80 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : éter de petróleo: acetato de étilo =9:6:1. Se obtiene un sólido de color naranjo, 211 mg, 0,48 mmol, con 72% rendimiento. Punto de fusión 172.3(d) °C. HRMS (M+) : m/z calculado C22H19N3O5S [M+] = 437.10454; encontrado = 437.10450. IR (KBr) : 1660.18, 1688.50 cnf1 C=0 (quinona) ; 1727.43 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.40 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.45 (c, 3J= 7.2 Hz, 2H, 6-CH2CH3) , 3.46 (s, 3H, 4-NCH3) , 3.78 (s, 3H, 2'-OCH3), 3.89 (s, 3H, 2-NCH3) , 6.13 (s, 1H, 9-H) , 7.08 (t, 3J=8.8 Hz, 2H, 5' y 3'), 7.54 (dd, 3J=7.1 Hz, 2H, 4' y 6' ) . 13C RMN (CDCI3, 100 MHz) : δ 12.2 (6-CH2CH3), 29.0 (4-NCH3), 30.2 (2- NCH3) , 31.6 (6-CH2CH3), 56.2 (2'-OCH3), 105.5 (10a), 112.1 (3'), 114.6 (6a), 120.9 (1'), 122.1 (5'), 127.6 (9), 133.1 (4'), 137.6 (6'), 147.4 (2'), 151.2 (10b), 152.8 (3), 154.8 (1), 158.6 (8), 160.1 (4a), 170.7 (6), 181.2 (10), 181.4 (7) . A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (420, 99 mg, 2.0 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 2-methoxythiophenol (90.67) is added dropwise mg, 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 80 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: petroleum ether: ethyl acetate = 9: 6: 1. An orange solid, 211 mg, 0.48 mmol, is obtained in 72% yield. Melting point 172.3 (d) ° C. HRMS (M +): m / z calculated C22H1 9 N 3 O5S [M +] = 437.10454; found = 437.10450. IR (KBr): 1660.18, 1688.50 cnf 1 C = 0 (quinone); 1727.43 cnf 1 C = 0 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.40 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.45 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.46 (s, 3H, 4-NCH 3 ), 3.78 (s, 3H, 2'-OCH 3 ), 3.89 (s, 3H, 2-NCH 3 ), 6.13 (s, 1H, 9-H), 7.08 (t, 3 J = 8.8 Hz, 2H, 5 'and 3'), 7.54 (dd, 3 J = 7.1 Hz, 2H, 4 'and 6'). 13 C NMR (CDCI3, 100 MHz): δ 12.2 (6-CH 2 CH 3 ), 29.0 (4-NCH 3 ), 30.2 (2- NCH 3 ), 31.6 (6-CH2CH3), 56.2 (2'-OCH 3 ) , 105.5 (10a), 112.1 (3 '), 114.6 (6a), 120.9 (1'), 122.1 (5 '), 127.6 (9), 133.1 (4'), 137.6 (6 '), 147.4 (2' ), 151.2 (10b), 152.8 (3), 154.8 (1), 158.6 (8), 160.1 (4a), 170.7 (6), 181.2 (10), 181.4 (7).
Ejemplo 5 Example 5
Obtención de 6-etil-8- ( (2-fluorofenil) tio) -2 , - dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona Obtaining 6-ethyl-8- ((2-fluorophenyl) thio) -2, - dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
Figure imgf000057_0001
Figure imgf000057_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (432, 91 mg, 2,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 2-fluorotiofenol (92,6 mg, 1,0 mmol) disuelto en CH2CI2 :MetOH=l : 1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 80 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : éter de petróleo: acetato de étilo =9:14:2. Se obtiene un sólido de color naranjo, 255 mg, 0,60 mmol, con 87% rendimiento. Punto de fusión 218.4 (d)°C. HRMS (M+) : m/z calculado C2iHi6FN304S [M+] = 425.08455; encontrado = 425.08460. IR (KBr) : 1660.18, 1684.96 cnf1 C=0 (quinona); 1727.43 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.38 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.43 (c, 3J= 7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.13 (s, 1H, 9-H) , 7.29 (dd, 3J=8.2 Hz, 2H, 5' y 3'), 7.52 (t, 3J=6.7 Hz, 2H, 4' y 6') · 13C RMN (CDCI3, 100 MHz) : δ 12.5 (6-CH2CH3), 29.5 (4-NCH3), 30.6 (2-NCH3), 32.1 (6- CH2CH3) , 105.7 (10a), 114.9 (d, 3J=18.6 Hz, 1'), 117.6 (d, 3J=22.3 Hz, 3'), 120.9 (6a), 126.3 (d, 3J=3.9 Hz, 5'), 128.4 (9), 133.9 (d, 3J=8.1 Hz, 4'), 137.9 (6'), 147.6 (10b), 151.5 (3), 153.2 (1), 154.4 (8), 158.8 (4a), 163.1 (d, 3J=251.5 Hz, 2'), 171.2 (6), 181.1 (10), 181.6 (7) . A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (432, 91 mg, 2.0 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 2-fluorothiophenol (92.6) is added dropwise mg, 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 80 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: petroleum ether: ethyl acetate = 9: 14: 2. An orange solid, 255 mg, 0.60 mmol, is obtained in 87% yield. Melting point 218.4 (d) ° C. HRMS (M +): m / z calculated C2iHi 6 FN 3 0 4 S [M +] = 425.08455; found = 425.08460. IR (KBr): 1660.18, 1684.96 cnf 1 C = 0 (quinone); 1727.43 cnf 1 C = 0 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.38 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.43 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2-NCH3), 6.13 (s, 1H, 9-H), 7.29 (dd, 3 J = 8.2 Hz, 2H, 5 'and 3 '), 7.52 (t, 3 J = 6.7 Hz, 2H, 4' and 6 ') · 13 C NMR (CDCI3, 100 MHz): δ 12.5 (6-CH 2 CH 3 ), 29.5 (4-NCH 3 ), 30.6 (2-NCH 3 ), 32.1 (6- CH 2 CH 3 ), 105.7 (10a), 114.9 (d, 3 J = 18.6 Hz, 1 '), 117.6 (d, 3 J = 22.3 Hz, 3 '), 120.9 (6a), 126.3 (d, 3 J = 3.9 Hz, 5'), 128.4 (9), 133.9 (d, 3 J = 8.1 Hz, 4 '), 137.9 (6'), 147.6 (10b ), 151.5 (3), 153.2 (1), 154.4 (8), 158.8 (4a), 163.1 (d, 3 J = 251.5 Hz, 2 '), 171.2 (6), 181.1 (10), 181.6 (7) .
Ejemplo 6 Example 6
Obtención de 8- ( (2-clorofenil) tio) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (6) Obtaining 8- ((2-chlorophenyl) thio) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (6)
Figure imgf000059_0001
Figure imgf000059_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (416,78 mg, 2,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 2-clorotiofenol (100,70 mg, 1,0 mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : éter de petróleo: acetato de étilo =9:14:2. Se obtiene un sólido de color naranjo, 240 mg, 0,54 mmol, con 82% rendimiento. Punto de fusión 220.8 (d) °C. HRMS (M+) : m/z calculado C2iHi6ClN304S [M+] = 441.05500; encontrado = 441.05521. IR (KBr) : 1660.18, 1677.88 cnf1 C=0 (quinona) ; 1720.35 cnf1 C=0 (uracilo) . ½ RMN (CDC13, 400 MHz) : δ 1.38 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.43 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4- NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.07 (s, 1H, 9-H) , 7.41 (t, 3J=7.5 Hz, 1H, 5'), 7.50 (t, 3J=7.7 Hz, 1H, 4'), 7.64 (m, 2H, 3' y 6' ) . 13C RMN (CDCI3, 100 MHz) : δ 12.1 (6-CH2CH3), 29.1 (4-NCH3), 30.2 (2-NCH3), 32.7 (6-CH2CH3), 105.9 (10a), 120.9 (6a), 126.9A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (416.78 mg, 2.0 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 2-chlorothiophenol (100.70) is added dropwise mg, 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: petroleum ether: ethyl acetate = 9: 14: 2. An orange solid, 240 mg, 0.54 mmol, is obtained in 82% yield. Melting point 220.8 (d) ° C. HRMS (M +): m / z calculated C 2 iHi 6 ClN 3 0 4 S [M +] = 441.05500; found = 441.05521. IR (KBr): 1660.18, 1677.88 cnf 1 C = 0 (quinone); 1720.35 cnf 1 C = 0 (uracil). ½ NMR (CDC1 3 , 400 MHz): δ 1.38 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.43 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4- NCH 3 ), 3.76 (s, 3H, 2-NCH3), 6.07 (s, 1H, 9-H), 7.41 (t, 3 J = 7.5 Hz, 1H, 5 '), 7.50 (t, 3 J = 7.7 Hz, 1H, 4'), 7.64 (m, 2H, 3 'and 6'). 13 C NMR (CDCI 3 , 100 MHz): δ 12.1 (6-CH 2 CH 3 ), 29.1 (4-NCH 3 ), 30.2 (2-NCH 3 ), 32.7 (6-CH 2 CH 3 ), 105.9 ( 10a), 120.9 (6a), 126.9
(1'), 128.3 (9), 128.9 (5'), 131.6 (3'), 132.9 (4'), 138.4 (6'), 140.3 (2'), 147.6 (10b), 151.5 (3), 153.2 (1), 154.2(1 '), 128.3 (9), 128.9 (5'), 131.6 (3 '), 132.9 (4'), 138.4 (6 '), 140.3 (2'), 147.6 (10b), 151.5 (3), 153.2 (1), 154.2
(8), 158.8 (4a), 171.2 (6), 181.1 (10), 181.6 (7) . (8), 158.8 (4a), 171.2 (6), 181.1 (10), 181.6 (7).
Ejemplo 7 Example 7
Obtención de 8- ( (2-bromofenil) tio) -6-etil-2 , - dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (7) . Obtaining 8- ((2-bromophenyl) thio) -6-ethyl-2, - dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (7).
Figure imgf000060_0001
Figure imgf000060_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (378, 69 mg, 2,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 2-bromotiofenol (119,62 mg, 1,0 mmol) disuelto en CH2C12 :MetOH= 1:1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 65 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : éter de petróleo: acetato de étilo =9:12:1. Se obtiene un sólido de color naranjo, 241 mg, 0,49 mmol, con 82% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (378, 69 mg, 2.0 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 2-bromothiophenol (119.62) is added dropwise mg, 1.0 mmol) dissolved in CH 2 C1 2 : MetOH = 1: 1 (30 ml) from a side-key burette a an approximate speed of lml / 30min for 16 hours. The reaction crude is purified with 65 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: petroleum ether: ethyl acetate = 9: 12: 1. An orange solid, 241 mg, 0.49 mmol, is obtained in 82% yield.
Punto de fusión 208.3 (d)°C. HRMS (M+) : m/z calculado C2iHi6BrN304S [M+] = 485.00449; encontrado = 485.00455. IR (KBr) : 1660.18, 1688.50 cnf1 C=0 (quinona); 1730.97 cnf1 C=0 (uracilo) . ½ RMN (CDC13, 400 MHz) : δ 1.37 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.41 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.42 (s, 3H, 4- NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.06 (s, 1H, 9-H) , 7.41 (dt, 3J=7.9 Hz, 2H, 5' y 4'), 7.64 (d, 3J=8.8 Hz, 1H, 6'), 7.79 (d, 3J=7.8 Hz, 1H, 3') . 13C RMN (CDCI3, 100 MHz) : δ 12.1 (6-CH2CH3), 29.1 (4-NCH3), 30.1 (2-NCH3) , 31.7 (6-CH2CH3), 105.6 (10a), 120.7 (6a), 127.9 (9), 128.9 (1'), 129.3 (5'), 130.8 (2'), 132.5 (4'), 134.7 (3'), 138.0 (6'), 147.3 (10b), 151.2 (3), 152.9 (1), 154.1 (8), 158.5 (4a), 170.9 (6), 180.7 (10), 181.2 (7) . Melting point 208.3 (d) ° C. HRMS (M +): m / z calculated C 2 iHi 6 BrN 3 0 4 S [M +] = 485.00449; found = 485.00455. IR (KBr): 1660.18, 1688.50 cnf 1 C = 0 (quinone); 1730.97 cnf 1 C = 0 (uracil). ½ NMR (CDC1 3 , 400 MHz): δ 1.37 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.41 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.42 (s, 3H, 4- NCH 3 ), 3.76 (s, 3H, 2-NCH 3 ), 6.06 (s, 1H, 9-H), 7.41 (dt, 3 J = 7.9 Hz, 2H, 5 ' and 4 '), 7.64 (d, 3 J = 8.8 Hz, 1H, 6'), 7.79 (d, 3 J = 7.8 Hz, 1H, 3 '). 13 C NMR (CDCI3, 100 MHz): δ 12.1 (6-CH 2 CH 3 ), 29.1 (4-NCH 3 ), 30.1 (2-NCH 3 ), 31.7 (6-CH 2 CH 3 ), 105.6 (10a ), 120.7 (6a), 127.9 (9), 128.9 (1 '), 129.3 (5'), 130.8 (2 '), 132.5 (4'), 134.7 (3 '), 138.0 (6'), 147.3 ( 10b), 151.2 (3), 152.9 (1), 154.1 (8), 158.5 (4a), 170.9 (6), 180.7 (10), 181.2 (7).
Ejemplo 8 Example 8
Obtención de 6-etil-2 , -dimetil-8- (m-toliltio) pirimido [ , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (8) . Obtaining 6-ethyl-2, -dimethyl-8- (m-tolylthio) pyrimido [, 5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (8).
Figure imgf000062_0001
Figure imgf000062_0001
Una solución con 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (452, 02 mg, 2,0 mmol) y tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : MetOH=l : 1 (10 mi), se adiciona mediante goteo una solución de 3-metiltiofenol (83,20 mg, l,0mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta a una velocidad aproximada de lml/30min por 16 horas. El crudo de la reacción se purifica con 50-90 g de Silica gel 0,063-0,2 mm utilizando como fase móvil una proporción adecuada de éter de petróleo, diclorometano y acetato de etilo. Se obtiene un sólido de color naranjo, 199 mg, 0,47 mmol, con 47% rendimiento. Punto de fusión 162.0 - 163.0°C. HRMS (M+) : m/z calculado C22H19N3O4 S [M+] = 421.10963; encontrado = 421.10960. IR (KBr) : 1561 cnf1 C=0 (quinona) ; 1661, 1682 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.37 (t, 3J=7.2 Hz, 3H, 6-CH2CH3) , 2.41 (s, 3H, 3'-CH3), 3.40 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4- NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.19 (s, 1H, 9-H) , 7.33 (m, 3H, 2', 5' y 6'), 7.42-7.37 (m, 1H, 4') · C RMN (CDCI3, 100 MHz) : δ 12.2 (6-CH2CH3) , 21.3 (3'-CH3), 29.1 (4-NCH3), 30.2 (2-NCH3), 31.7 (6-CH2CH3) , 105.5 (10a), 120.6 (6a), 126.9 (1'), 127.9 (9),A solution with 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone (1) (452.0 mg, 2.0 mmol) and cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 3-methylthiophenol (83.20 mg) is added dropwise , l, 0mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 50-90 g of 0.063-0.2 mm Silica gel using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase. An orange solid, 199 mg, 0.47 mmol, is obtained in 47% yield. Melting point 162.0 - 163.0 ° C. HRMS (M +): m / z calculated C22H1 9 N 3 O4 S [M +] = 421.10963; found = 421.10960. IR (KBr): 1561 cnf 1 C = 0 (quinone); 1661, 1682 cnf 1 C = 0 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.37 (t, 3 J = 7.2 Hz, 3H, 6-CH 2 CH 3 ), 2.41 (s, 3H, 3'-CH 3 ), 3.40 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ), 3.44 (s, 3H, 4- NCH 3 ), 3.76 (s, 3H, 2-NCH 3 ), 6.19 (s, 1H, 9-H), 7.33 (m, 3H, 2 ', 5' and 6 '), 7.42-7.37 (m, 1H, 4') C NMR (CDCI 3 , 100 MHz): δ 12.2 (6-CH 2 CH 3 ), 21.3 (3'-CH 3 ), 29.1 (4-NCH 3 ), 30.2 (2-NCH 3 ), 31.7 (6-CH 2 CH 3 ), 105.5 (10a), 120.6 (6a), 126.9 (1 '), 127.9 (9),
130.3 (4'), 131.6 (5'), 132.7 (6'), 136.1 (2'), 140.6 (3'), 147.4 (10b), 151.1 (3), 152.8 (1), 156.9 (8), 158.5 (4a), 170.8 (6) , 180.9 (7) , 181.4 (10) . 130.3 (4 '), 131.6 (5'), 132.7 (6 '), 136.1 (2'), 140.6 (3 '), 147.4 (10b), 151.1 (3), 152.8 (1), 156.9 (8), 158.5 (4a), 170.8 (6), 180.9 (7), 181.4 (10).
Ejemplo 9 Example 9
Obtención de 6-etil-8- (3-metoxitiofenil) dimetilpirimido [ , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (9) . Obtaining 6-ethyl-8- (3-methoxythiophenyl) dimethylpyrimido [, 5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (9).
Figure imgf000063_0001
Figure imgf000063_0001
Una solución con 6-etil-2 , 4 -dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (598, 56 mg, 2,0 mmol) y tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : MetOH=l : 1 (10 mi), se adiciona mediante goteo una solución de 3-metoxitiofenol (140,20 mg, l,0mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta a una velocidad aproximada de lml/30min por 16 horas. El crudo de la reacción se purifica con 50-90 g de Silica gel 0,063-0,2 mm utilizando como fase móvil una proporción adecuada de éter de petróleo, diclorometano y acetato de etilo. Se obtiene un sólido de color naranjo, 288,7 mg, 0,66 mmol, con 66% rendimiento. A solution with 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone (1) (598, 56 mg, 2.0 mmol) and cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 10 (10 ml), a solution of 3-methoxythiophenol (140.20 mg) is added dropwise , l, 0mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a burette at a speed Approximate lml / 30min for 16 hours. The reaction crude is purified with 50-90 g of 0.063-0.2 mm Silica gel using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase. An orange solid, 288.7 mg, 0.66 mmol, is obtained in 66% yield.
Punto de fusión 179.5 - 180.5°C. HRMS (M+) : m/z calculado C22H19N3O5S [M+] = 437.10454; encontrado = 437.10449. IR (KBr) : 1560, 1579 cnf1 C=0 (quinona) ; 1670 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.37 (t, 3J=7.2 Hz, 3H, 6-CH2CH3) , 3.40 (c, 2J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 3'- OCH3) , 3.85 (s, 3H, 2-NCH3) , 6.23 (s, 1H, 9-H) , 7.07-7.02 (m, 2H, 2' y 6'), 7.12 (m 1H, 4'), 7.42 (t, 3J=7.7 Hz, 1H, 5') · 13C RMN (CDCI3, 100 MHz) : δ 12.2 (6-CH2CH3), 29.1 (4-NCH3), 30.2 (2- NCH3) , 31.7 (6-CH2CH3), 55.5 (3'-OCH3), 105.5 (10a), 116.7 (4'), 120.6 (6a), 120.7 (2'), 127.7 (6'), 128.0 (1'), 128.1 (9), 131.1 (5'), 147.3 (10b), 151.5(3) 152.8 (1), 156.06 (8), 158.4 (4a), 160.8 (3'), 170.7 (6), 180.8 (7), 181.4 (10) . Ejemplo 10 Melting point 179.5 - 180.5 ° C. HRMS (M +): m / z calculated C22H1 9 N 3 O5S [M +] = 437.10454; found = 437.10449. IR (KBr): 1560, 1579 cnf 1 C = 0 (quinone); 1670 cnf 1 C = 0 (uracil). ½ NMR (CDCI3, 400 MHz): δ 1.37 (t, 3 J = 7.2 Hz, 3H, 6-CH 2 CH 3 ), 3.40 (c, 2 J = 7.2 Hz, 2H, 6-CH 2 CH3), 3.44 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 3'- OCH 3 ), 3.85 (s, 3H, 2-NCH 3 ), 6.23 (s, 1H, 9-H), 7.07-7.02 (m, 2H, 2 'and 6'), 7.12 (m 1H, 4 '), 7.42 (t, 3 J = 7.7 Hz, 1H, 5') · 13 C NMR (CDCI3, 100 MHz): δ 12.2 ( 6-CH 2 CH 3 ), 29.1 (4-NCH 3 ), 30.2 (2- NCH 3 ), 31.7 (6-CH 2 CH 3 ), 55.5 (3'-OCH 3 ), 105.5 (10a), 116.7 ( 4 '), 120.6 (6a), 120.7 (2'), 127.7 (6 '), 128.0 (1'), 128.1 (9), 131.1 (5 '), 147.3 (10b), 151.5 (3) 152.8 (1 ), 156.06 (8), 158.4 (4a), 160.8 (3 '), 170.7 (6), 180.8 (7), 181.4 (10). Example 10
Obtención de 6-etil-8- (3- luorotio enil) -2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (10) .
Figure imgf000065_0001
Obtaining 6-ethyl-8- (3- luoroth enyl) -2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (10).
Figure imgf000065_0001
Una solución con 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (589, 56 mg, 2,0 mmol) y tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : MetOH=l : 1 (10 mi), se adiciona mediante goteo una solución de 3-fluortiofenol (128,17 mg, l,0mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta a una velocidad aproximada de lml/30min por 16 horas. El crudo de la reacción se purifica con 50-90 g de Silica gel 0,063-0,2 mm utilizando como fase móvil una proporción adecuada de éter de petróleo, diclorometano y acetato de etilo. Se obtiene un sólido de color naranjo, 302,1 mg, 0,71 mmol, con 71% rendimiento. Punto de fusión 170 - 171°C. HRMS (M+) : m/z calculado C2iHi6FN304S [M+] = 425.08455; encontrado = 425.08457. IR (KBr) : 1563 cnf1 C=0 (quinona) ; 1667, 1683 cnf1 C=0 en 1 y 3 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.37 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.42 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.21 (s, 1H, 9-H) , 7.26 (d, 3J=8.4 Hz, 2H, 4' y 6'), 7.35 (d, J=7.6 Hz, 1H, 2'), 7.51(c, J=7.5 Hz, 1H, 5') · ±JC RMN (CDCI3, 100 MHz) : δ 12.4 (6-CH2CH3), 29.4 (4-NCH3), 30.5 (2-NCH3) , 32.1 (6-CH2CH3), 105.8 (10a), 118.16 (d, 1C, 1J=20.9 Hz, 3'), 120.8 (6a), 122.66 (d, 1C 1J=22.1 Hz, 2') 128.4 (9), 129.25 (d, 1C 1J=1.6 Hz, 1'), 131.76 (dd, 1C ^=34.4, 5.7 Hz, 4') 147.5 (10b), 151.4 (3), 153.1 (1), 156.1 (8), 158.7 (4a), 162.3 (6?) ,164.8 (5') 171,2 (6), 180.9 (7), 181.6 (10) . A solution with 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (589.56 mg, 2.0 mmol) and cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 10 (10 ml), a solution of 3-fluortiophenol (128.17 mg) is added dropwise , l, 0mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 50-90 g of 0.063-0.2 mm Silica gel using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase. An orange solid, 302.1 mg, 0.71 mmol, is obtained in 71% yield. Melting point 170-171 ° C. HRMS (M +): m / z calculated C 2 iHi 6 FN 3 0 4 S [M +] = 425.08455; found = 425.08457. IR (KBr): 1563 cnf 1 C = 0 (quinone); 1667, 1683 cnf 1 C = 0 in 1 and 3 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.37 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.42 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2-NCH 3 ), 6.21 (s, 1H, 9-H), 7.26 (d, 3 J = 8.4 Hz, 2H, 4 ' and 6 '), 7.35 (d, J = 7.6 Hz, 1H, 2'), 7.51 (c, J = 7.5 Hz, 1H, 5 ') ± J C NMR (CDCI3, 100 MHz): δ 12.4 (6-CH 2 CH 3 ), 29.4 (4-NCH 3 ), 30.5 (2-NCH3), 32.1 (6-CH2CH3), 105.8 (10a), 118.16 (d, 1C, 1 J = 20.9 Hz, 3 '), 120.8 (6a), 122.66 (d, 1C 1 J = 22.1 Hz, 2') 128.4 (9), 129.25 (d, 1C 1 J = 1.6 Hz, 1 '), 131.76 (dd, 1C ^ = 34.4, 5.7 Hz, 4') 147.5 (10b), 151.4 (3), 153.1 (1), 156.1 (8), 158.7 (4a), 162.3 (6?), 164.8 (5 ') 171.2 (6), 180.9 (7), 181.6 (10).
Ejemplo 11 Example 11
Obtención de 8- (3-clorotiofenil) -6-etil dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (11) · Obtaining 8- (3-chlorothiophenyl) -6-ethyl dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (11) ·
Figure imgf000066_0001
Una solución con 6-etil-2 , 4 -dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (598, 6 mg, 2,0 mmol) y tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se adiciona mediante goteo una solución de 3-clorotiofenol (144,62 mg, l,0mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta a una velocidad aproximada de lml/30min por 16 horas. El crudo de la reacción se purifica con 50-90 g de Silica gel 0, 063-0, 2 rom utilizando como fase móvil una proporción adecuada de éter de petróleo, diclorometano y acetato de etilo. Se obtiene un sólido de color naranjo, 256,3 mg, 0,58 mmol, con 58% rendimiento.
Figure imgf000066_0001
A solution with 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone (1) (598.6 mg, 2.0 mmol) and cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 10 (10 ml), a solution of 3-chlorothiophenol (144.62 mg) is added dropwise , l, 0mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a burette at an approximate rate of lml / 30min for 16 hours. The reaction crude it is purified with 50-90 g of Silica gel 0.063-0.2 rom using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase. An orange solid, 256.3 mg, 0.58 mmol, is obtained in 58% yield.
Punto de fusión 156.1 - 157.1° C. HRMS (M+) : m/z calculado C2iHi6ClN304S [M+] = 441.05500; encontrado = 441.05514. IR (KBr) : 1558 cnf1 C=0 (quinona) ; 1662, 1681 cnf1 C=0 (uracilo) . 1H RMN (CDCI3, 400 MHz) : δ 1.37 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.41 (c, 2J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.21 (s, 1H, 9-H) , 7.47 (c, 2J=Hz, 2H, 6' y 5'), 7,52 (d, 2J=7.1 Hz, 1H, 4') 7.55 (s, 1H, 2') · 13C RMN (CDCI3, 100 MHz) : δ 12.1 (6-CH2CH3), 29.1 (4-NCH3), 30.2 (2- NCH3) , 31.8 (6-CH2CH3), 105.5 (10a), 120.4 (6a), 128.1 (9), 129.1 (3') 131.1 (6') 131.5 (4'), 133.9 (5'), 135.4 (2'), 136(3') 147.2 (10b), 151.1 (3), 152.8 (1), 155.8 (8), 158.4 (4a), 170.9 (6), 180.5 (7), 181.3 (10) . Melting point 156.1 - 157.1 ° C. HRMS (M +): m / z calculated C2iHi 6 ClN 3 0 4 S [M +] = 441.05500; found = 441.05514. IR (KBr): 1558 cnf 1 C = 0 (quinone); 1662, 1681 cnf 1 C = 0 (uracil). 1 H NMR (CDCI 3 , 400 MHz): δ 1.37 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.41 (c, 2 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2-NCH3), 6.21 (s, 1H, 9-H), 7.47 (c, 2 J = Hz, 2H, 6 'and 5 '), 7.52 (d, 2 J = 7.1 Hz, 1H, 4') 7.55 (s, 1H, 2 ') · 13 C NMR (CDCI3, 100 MHz): δ 12.1 (6-CH 2 CH 3 ) , 29.1 (4-NCH 3 ), 30.2 (2- NCH 3 ), 31.8 (6-CH 2 CH3), 105.5 (10a), 120.4 (6a), 128.1 (9), 129.1 (3 ') 131.1 (6' ) 131.5 (4 '), 133.9 (5'), 135.4 (2 '), 136 (3') 147.2 (10b), 151.1 (3), 152.8 (1), 155.8 (8), 158.4 (4a), 170.9 (6), 180.5 (7), 181.3 (10).
Ejemplo 12 Example 12
Obtención de 8- (3-bromotiofenil) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (12) .
Figure imgf000068_0001
Obtaining 8- (3-bromothiophenyl) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (12).
Figure imgf000068_0001
Una solución con 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (598, 6 mg, 2,0 mmol) y tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se adiciona mediante goteo una solución de 3-bromotiofenol (189,07 mg, l,0mmol) disuelto en CH2CI2 :MetOH= 1:1 (30 mi) desde una bureta a una velocidad aproximada de lml/30min por 16 horas. El crudo de la reacción se purifica con 50-90 g de Silica gel 0,063-0,2 mm utilizando como fase móvil una proporción adecuada de éter de petróleo, diclorometano y acetato de etilo. Se obtiene un sólido de color naranjo, 398,8 mg, 0,82 mmol, con 82% rendimiento. Punto de fusión 138.3 - 139.3°C. HRMS (M+) : m/z calculado C2iHi6BrN304S [M+] = 485.00449; encontrado = 485.00453. IR (KBr) : 1559 cnf1 C=0 (quinona) ; 1668 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.3 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.43-3.38 (c, 2J=Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2- NCH3) , 6.21 (s, 1H, 9-H) , 7.47 (c, 2J=Hz, 2H, 4' y 5'), 7.52 (d, J=7.1 Hz, 1H, 6') 7.55 (s, 1H, 2') · 13C RMN (CDC13, 100 MHz) : δ 12.5 (6-CH2CH3), 29.4 (4-NCH3), 30.5 (2-NCH3), 32.1 (6- CH2CH3) , 105.8 (10a), 120.7 (6a), 124.2 (1'), 128.5 (9), 129.7 (3'), 132.0 (5'), 134.3 (6'), 134.6 (4'), 138.5 (2'), 147.5 (10b) 151.4 (3), 153.1 (1), 156.1 (8) 158.7 (4a), 171.2 (6), 180.8 (7) , 181.6 (10) . A solution with 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1,3,7,10 (2H, 4JJ) -tetraone (1) (598.6 mg, 2.0 mmol) and cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 3-bromothiophenol (189.07 mg) is added dropwise , l, 0mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 50-90 g of 0.063-0.2 mm Silica gel using a suitable proportion of petroleum ether, dichloromethane and ethyl acetate as the mobile phase. An orange solid, 398.8 mg, 0.82 mmol, is obtained in 82% yield. Melting point 138.3 - 139.3 ° C. HRMS (M +): m / z calculated C 2 iHi 6 BrN 3 0 4 S [M +] = 485.00449; found = 485.00453. IR (KBr): 1559 cnf 1 C = 0 (quinone); 1668 cnf 1 C = 0 (uracil). ½ NMR (CDCI3, 400 MHz): δ 1.3 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.43-3.38 (c, 2 J = Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2- NCH 3 ), 6.21 (s, 1H, 9-H), 7.47 (c, 2 J = Hz, 2H, 4 'and 5 '), 7.52 (d, J = 7.1 Hz, 1H, 6') 7.55 (s, 1H, 2 ') · 13 C NMR (CDC1 3 , 100 MHz): δ 12.5 (6-CH 2 CH 3 ), 29.4 (4-NCH 3 ), 30.5 (2-NCH 3 ), 32.1 (6- CH 2 CH 3 ), 105.8 (10a), 120.7 (6a), 124.2 (1 '), 128.5 (9), 129.7 (3'), 132.0 (5 '), 134.3 (6'), 134.6 (4 '), 138.5 (2'), 147.5 (10b) 151.4 (3), 153.1 (1), 156.1 (8) 158.7 (4a), 171.2 (6), 180.8 (7), 181.6 (10).
Ejemplo 13 Example 13
Obtención de 6-etil-2 , -dimetil-8- (p-toliltio) pirimido [ , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (13) . Obtaining 6-ethyl-2, -dimethyl-8- (p-tolylthio) pyrimido [, 5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (13).
Figure imgf000069_0001
Figure imgf000069_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (300, 13 mg, 2,1 mmol), tricloruro de cerio(III) heptahidratado (5 % mol de 1) en una mezcla de CH2CI2 :MetOH=3, 5 : 5 (8 mi), se adiciona mediante goteo una solución de 4-Metiltiofenol (60,8mg, 1,0 mmol) disuelto en CH2CI2 :MetOH= 3,5:5 (34 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 14 horas. El crudo de reacción se purifica con 50 g de silica gel (0, 040-0, 063 mm) utilizando como fase móvil éter de petróleo: diclorometano : acetato de étilo= 1,5:0,5:0,5. Se obtiene un sólido de color naranjo, 174,5 mg, 0,41 mmol, con 87,5% rendimiento . A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone (1) (300, 13 mg, 2.1 mmol), Cerium (III) trichloride heptahydrate (5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 3: 5: 5 (8 ml), a solution of 4-Methylthiophenol (60.8mg, is added dropwise 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 3.5: 5 (34 ml) from a side key burette at an approximate rate of lml / 30min for 14 hours. The reaction crude is purified with 50 g of silica gel (0.040-0.063 mm) using petroleum ether as the mobile phase: dichloromethane: ethyl acetate = 1.5: 0.5: 0.5. An orange solid, 174.5 mg, 0.41 mmol, is obtained in 87.5% yield.
Punto de fusión 191.0 - 192.3°C. HRMS (M+) : m/z calculado C22H19N3O4 S [M+] = 421.10963; encontrado = 421.10954. IR (KBr) : 1662.34, 1687.48 cnf1 C=0 (quinona); 1725.98 cnf1 C=0 (uracilo) . ½ RMN (CDCI3, 400 MHz) : δ 1.37 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 2.42 (s, 3H, 4'-CH3), 3.42 (c, 3J=7.3 Hz, 2H, 6-CH2CH3) , 3.43 (s, 3H, 4-NCH3) , 3.75 (s, 3H, 2-NCH3) , 6.17 (s, 1H, 9-H) , 7.31 (d, 3J=8.0 Hz, 2H, 3' y 5'), 7.40 (d, 3J =8.0 Hz, 2H, 2' y 6') · 13C RMN (CDCI3, 100 MHz) : δ 12.3 (6-CH2CH3), 21.5 (4'-CH3), 29.2 (4-NCH3), 30.3 (2-NCH3) , 31.8 (6-CH2CH3), 105.5 (10b), 120.7 (7a), 123.6 (1'), 127.9 (9), 131.4 (2C, 3' y 5'), 135.7 (2C, 2' y 6'), 141.4 (4'), 147.5 (10a), 151.2 (3), 152.8 (1), 157.2 (8), 158.8 (4a), 171.1 (6), 181.3 (7), 181.8 (10) . Melting point 191.0 - 192.3 ° C. HRMS (M +): m / z calculated C22H1 9 N 3 O4 S [M +] = 421.10963; found = 421.10954. IR (KBr): 1662.34, 1687.48 cnf 1 C = 0 (quinone); 1725.98 cnf 1 C = 0 (uracil). ½ NMR (CDCI 3 , 400 MHz): δ 1.37 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 2.42 (s, 3H, 4'-CH 3 ), 3.42 (c, 3 J = 7.3 Hz, 2H, 6-CH 2 CH 3 ), 3.43 (s, 3H, 4-NCH 3 ), 3.75 (s, 3H, 2-NCH 3 ), 6.17 (s, 1H, 9-H), 7.31 (d, 3 J = 8.0 Hz, 2H, 3 'and 5'), 7.40 (d, 3 J = 8.0 Hz, 2H, 2 'and 6') · 13 C NMR (CDCI3, 100 MHz): δ 12.3 ( 6-CH 2 CH 3 ), 21.5 (4'-CH 3 ), 29.2 (4-NCH 3 ), 30.3 (2-NCH 3 ), 31.8 (6-CH 2 CH 3 ), 105.5 (10b), 120.7 ( 7a), 123.6 (1 '), 127.9 (9), 131.4 (2C, 3' and 5 '), 135.7 (2C, 2' and 6 '), 141.4 (4'), 147.5 (10a), 151.2 (3 ), 152.8 (1), 157.2 (8), 158.8 (4a), 171.1 (6), 181.3 (7), 181.8 (10).
Ejemplo 14 Example 14
Obtención de 6-etil-8- (4-metoxitiofenil) -2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (14) Obtaining 6-ethyl-8- (4-methoxythiophenyl) -2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (14)
Figure imgf000071_0001
Figure imgf000071_0001
Una Solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (429, 4mg, 2,lmmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=3, 5 : 5 (8 mi), se adiciona mediante goteo una solución de 4-Metoxitiofenol ( 95, 03mg, 1 , Ommol ) enA solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone (1) (429, 4mg, 2, lmmol), trichloride Cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 3: 5: 5 (8 ml), a solution of 4-Methoxythiophenol (95, 03mg, is added dropwise) 1, Ommol) in
CH2CI2 :MetOH=3, 5 : 5 (34 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min esto por 14 horas . El crudo de reacción se purifica con 60 g de silica gel (0, 040- 0,063 mm) utilizando como fase móvil éter de petróleo : diclorometano : acetato de etilo=l , 5 : 1 , 5 : 0 , 5. Se obtiene un sólido de color rojizo, 163 mg, 0,37 mmol, con 82 % rendimiento. CH 2 CI 2 : MetOH = 3, 5: 5 (34 mi) from a side key burette at an approximate speed of lml / 30min this for 14 hours. The reaction crude is purified with 60 g of silica gel (0.040-0.063 mm) using as petroleum ether mobile phase: dichloromethane: ethyl acetate = 1.5, 5: 1, 5: 0, 5. A solid is obtained reddish, 163 mg, 0.37 mmol, with 82% yield.
Punto de fusión 198.9 - 201.5°C. HRMS (M+) : m/z calculado C22H19N3O5S [M+] = 437.10454; encontrado = 437.10454. IR (KBr) : 1662.34, 1689.34 cnf1 C=0 (quinona) ; 1725.98 cnf1 C=0 (uracilo) . ½ RMN (CDC13, 400 MHz) : δ 1.36 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.41 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.43 (s, 3H, 4-NCH3) , 3.75 (s, 3H, 4'-OCH3), 3.86 (s, 3H, 2-NCH3) , 6.15 (s, 1H, 9-H) , 7.23Melting point 198.9 - 201.5 ° C. HRMS (M +): m / z calculated C22H1 9 N 3 O5S [M +] = 437.10454; found = 437.10454. IR (KBr): 1662.34, 1689.34 cnf 1 C = 0 (quinone); 1725.98 cnf 1 C = 0 (uracil). ½ NMR (CDC13, 400 MHz): δ 1.36 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.41 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ), 3.43 (s, 3H, 4-NCH 3 ), 3.75 (s, 3H, 4'-OCH 3 ), 3.86 (s, 3H, 2-NCH 3 ), 6.15 (s, 1H, 9-H), 7.23
(dd, 3'4J=165.7, 8.7 Hz, 4H) . 13C RMN (CDCI3, 100 MHz) : δ 12.3(dd, 3 ' 4 J = 165.7, 8.7 Hz, 4H). 13 C NMR (CDCI 3 , 100 MHz): δ 12.3
(6-CH2CH3), 29.2 (4-NCH3), 30.3 (2-NCH3), 31.8 (6-CH2CH3), 55.7(6-CH 2 CH 3 ), 29.2 (4-NCH 3 ), 30.3 (2-NCH 3 ), 31.8 (6-CH 2 CH 3 ), 55.7
(4'-OCH3), 105.5 (10b), 116.5, 117.3 (1'), 120.7 (6a), 127.9 (9), 137.6, 147.5 (10a), 151.2 (3), 152.8 (1), 157.6 (8), 158.5 (4a), 161.7 (4'), 171.1 (6), 181.4 (7), 181.8 (10) . (4'-OCH 3 ), 105.5 (10b), 116.5, 117.3 (1 '), 120.7 (6a), 127.9 (9), 137.6, 147.5 (10a), 151.2 (3), 152.8 (1), 157.6 ( 8), 158.5 (4a), 161.7 (4 '), 171.1 (6), 181.4 (7), 181.8 (10).
Ejemplo 15 Example 15
Obtención de 6-etil-8- (4-fluorotiofenil) -2 , - dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (15) . Obtaining 6-ethyl-8- (4-fluorothiophenyl) -2, - dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (15).
Figure imgf000072_0001
Una Solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (424, 42mg, 2,lmmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=3, 5 : 5 (8 mi), se adiciona mediante goteo una solución de 4-fluorotiofenol (128,17mg, l,0mmol) disuelto en CH2CI2 :MetOH=3, 5 : 5 (34 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min esto por 14 horas. El crudo de reacción se purifica con 65 g de silica gel (0, 040- 0,063 mm) utilizando fase móvil éter de petróleo : diclorometano : acetato de étilo=3 , 0 : 0 , 5 : 0 , 5. Se obtiene un sólido de color naranjo, 122,1 mg, 0,28 mmol, con 61,1 % rendimiento.
Figure imgf000072_0001
A solution of 6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (424, 42mg, 2, lmmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 3: 5: 5 (8 ml), a solution of 4-fluorothiophenol (128.17 mg, is added dropwise l, 0mmol) dissolved in CH 2 CI 2 : MetOH = 3, 5: 5 (34 mi) from a side key burette a an approximate speed of lml / 30min this for 14 hours. The reaction crude is purified with 65 g of silica gel (0.040-0.063 mm) using mobile phase petroleum ether: dichloromethane: ethyl acetate = 3.0: 0.5: 0.5: 5. A solid of orange color, 122.1 mg, 0.28 mmol, with 61.1% yield.
Punto de fusión 194.9 - 195.4°C. HRMS (M+) : m/z calculado C2iHi6FN304S [M+] = 425.08455; encontrado = 425.08462. IR (KBr) : 1660.41, 1675.84 cnf1 C=0 (quinona) ; 1720.19 cnf1 C=0 (uracilo) . ½ RMN (CDC13, 400 MHz) : δ 1.37 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.42 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.15 (s, 1H, 9-H) , 7.22 (d, 3J=8.4 Hz, 2H, 2' y 6'), 7.52 (d, 3J=8.4 Hz, 2H, 3' y 5') · 13C RMN (CDC13, 100 MHz) : δ 12.53 (6-CH2CH3), 29.47 (4-NCH3), 30.60 (2-NCH3), 32.13 (6-CH2CH3), 105.83 (10b), 118.24 (d, 2C, 2J=22 Hz, 3' y 5') , 120.87 (6a), 122.85 (1'), 128.29 (9), 138.29 (d, 2C, 3J=8 Hz, 2' y 6'), 147.6 (10a), 151.45 (3), 153.16 (1), 156.88 (8), 158.8 (4a), 164.63 (d, 1C, 1J=2 l Hz, 4'), 171,21 (6), 181.9 (7) , 181.68 (10) . Melting point 194.9 - 195.4 ° C. HRMS (M +): m / z calculated C 2 iHi 6 FN 3 0 4 S [M +] = 425.08455; found = 425.08462. IR (KBr): 1660.41, 1675.84 cnf 1 C = 0 (quinone); 1720.19 cnf 1 C = 0 (uracil). ½ NMR (CDC1 3 , 400 MHz): δ 1.37 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.42 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2-NCH3), 6.15 (s, 1H, 9-H), 7.22 (d, 3 J = 8.4 Hz, 2H, 2 'and 6 '), 7.52 (d, 3 J = 8.4 Hz, 2H, 3' and 5 ') · 13 C NMR (CDC1 3 , 100 MHz): δ 12.53 (6-CH 2 CH 3 ), 29.47 (4-NCH 3 ), 30.60 (2-NCH 3 ), 32.13 (6-CH 2 CH 3 ), 105.83 (10b), 118.24 (d, 2C, 2 J = 22 Hz, 3 'and 5'), 120.87 (6a), 122.85 (1 '), 128.29 (9), 138.29 (d, 2C, 3 J = 8 Hz, 2' and 6 '), 147.6 (10a), 151.45 (3), 153.16 (1), 156.88 (8), 158.8 (4a), 164.63 (d, 1C, 1 J = 2 l Hz, 4 '), 171.21 (6), 181.9 (7), 181.68 (10).
Ejemplo 16 Obtención de 8- (4-clorotiofenil) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (16) Example 16 Obtaining 8- (4-chlorothiophenyl) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (16)
Figure imgf000074_0001
Figure imgf000074_0001
Una Solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (424, 42mg, 2,lmmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=3, 5 : 5 (8 mi), se adiciona mediante goteo una solución de 4-Clorotiofenol (98,80mg, l,0mmol) disuelto en CH2CI2 :MetOH=3, 5 : 5 (34 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min esto por 14 horas aproximadamente. El crudo de reacción se purifica con 60 g de silica gel (0, 040-0, 063 rom) utilizando fase móvil éter de petróleo : diclorometano : acetato de étilo=l , 5 : 0 , 5 : 0 , 5. Se obtiene un sólido de color naranjo, 221,5 mg, 0,5 mmol, con 75% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (424, 42mg, 2, lmmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 3: 5: 5 (8 ml), a solution of 4-Chlorothiophenol (98.80 mg, is added dropwise 1, 0mmol) dissolved in CH 2 CI 2 : MetOH = 3, 5: 5 (34 ml) from a side key burette at an approximate speed of lml / 30min this for approximately 14 hours. The reaction crude is purified with 60 g of silica gel (0.040-0, 063 rom) using mobile phase petroleum ether: dichloromethane: ethyl acetate = 1.5, 0.5: 0.5: 5. A Orange solid, 221.5 mg, 0.5 mmol, with 75% yield.
Punto de fusión 196.5 - 198.3°C. HRMS (M+) : m/z calculado C2iHi6ClN304S [M+] = 441.05500; encontrado = 441.05491. IR (KBr) : 1656.55, 1675.84 cnf1 C=0 (quinona) ; 1722.12 cnf1 C=0 (uracilo) . ½ RMN (CDC13, 400 MHz) : δ 1.36 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.41 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4- NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.17 (s, 1H, 9-H) , 7.49 (m, 4H, 2' 3' 5' y 6'-H) . 13C RMN (CDCI3, 100 MHz) : δ 12.2 (6-CH2CH3), 29.2 (4-NCH3), 30.3 (2-NCH3) , 31.9 (6-CH2CH3), 105.6 (10b), 120.6 (6a), 125.8, 128.1 (9), 130.88, 137.09, 137.54, 147.3 (10a), 151.2 (3), 152.9 (1), 156.2 (8), 158.5 (4a), 170.9 (6), 180.7 (7) , 181.3 (10) . Melting point 196.5 - 198.3 ° C. HRMS (M +): m / z calculated C 2 iHi 6 ClN 3 0 4 S [M +] = 441.05500; found = 441.05491. GO (KBr): 1656.55, 1675.84 cnf 1 C = 0 (quinone); 1722.12 cnf 1 C = 0 (uracil). ½ NMR (CDC1 3 , 400 MHz): δ 1.36 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.41 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ) , 3.44 (s, 3H, 4- NCH 3 ), 3.76 (s, 3H, 2-NCH 3 ), 6.17 (s, 1H, 9-H), 7.49 (m, 4H, 2 '3' 5 'and 6 '-H). 13 C NMR (CDCI3, 100 MHz): δ 12.2 (6-CH 2 CH 3 ), 29.2 (4-NCH 3 ), 30.3 (2-NCH 3 ), 31.9 (6-CH 2 CH 3 ), 105.6 (10b ), 120.6 (6a), 125.8, 128.1 (9), 130.88, 137.09, 137.54, 147.3 (10a), 151.2 (3), 152.9 (1), 156.2 (8), 158.5 (4a), 170.9 (6), 180.7 (7), 181.3 (10).
Ejemplo 17 Example 17
Obtención de 8- (4-bromotiofenil) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (17) Obtaining 8- (4-bromothiophenyl) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (17)
Figure imgf000075_0001
Figure imgf000075_0001
17  17
Una 6-etil-2, 4-dimetilpirimido [4, 5-c] isoquinolin-A 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-
1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (424, 42mg, 2,lmmol), tricloruro de cerio Heptahidratado (0,5% mol de 1) en una mezcla de CH2C I2 :MetOH=3, 5 : 5 (8 mi), se adiciona mediante goteo una solución de 4-bromotiofenol (98,80mg, l,0mmol) disuelto en CH2C I2 :MetOH=3, 5 : 5 (34 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min esto por 14 horas. El crudo de reacción se purifica con 75 g de silica gel (0, 040- 0,063 mm) utilizando fase móvil 4,0:0,5:0,5 de éter de petróleo : diclorometano : acetato de étilo. Se obtiene un sólido de color naranjo, 201,7 mg, 0,41 mmol, con 68,1 % rendimiento. Punto de fusión 197.9 - 198.7°C. HRMS (M+) : m/z calculado C2 iHi6BrN304S [M+] = 485.00449; encontrado = 485.00438. IR (KBr) : 1656.55, 1677.77 cnf1 C=0 (quinona); 1722.12 cnf1 C=0 (uracilo) . ½ RMN (CDC13, 400 MHz) : δ 1.36 (t, 3J=7.3 Hz, 3H, 6- CH2CH3 ) , 3.41 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) , 3.44 (s, 3H, 4- NCH3) , 3.75 (s, 3H, 2-NCH3) , 6.18 (s, 1H, 9-H) , 7.41 (d, 3J=8.4 Hz, 2H, 2' y 6'), 7.66 (d, 3J=8.4 Hz, 2H, 3' y 5') · 13C RMN (CDCI3, 100 MHz) : δ 12.2 (6-CH2CH3), 29.2 (4-NCH3), 30.3 (2- NCH3) , 31.9 (6- CH2CH3 ) , 105.5 (10b), 120.5 (6a), 125.8 (4'), 126.4 (1'), 128.1 (9), 133.9 (2C, 3' y 5'), 137.3 (2C, 2' y 6'), 147.3 (10a), 151.2 (3), 152.9 (1), 156.0 (8), 158.5 (4a), 170.9 (6) , 180.7 (7) , 181.4 (10) . 1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (424, 42mg, 2, lmmol), cerium trichloride Heptahydrate (0.5 mol% of 1) in a mixture of CH2C I2: MetOH = 3: 5: 5 (8 ml), a solution of 4-bromothiophenol (98.80 mg, l, 0mmol) dissolved in CH2C I2: MetOH = 3, 5: 5 (34 ml) is added dropwise from a side key burette at an approximate speed of lml / 30min this for 14 hours. The reaction crude is purified with 75 g of silica gel (0.040-0.063 mm) using mobile phase 4.0: 0.5: 0.5 petroleum ether: dichloromethane: ethyl acetate. An orange solid, 201.7 mg, 0.41 mmol, is obtained in 68.1% yield. Melting point 197.9 - 198.7 ° C. HRMS (M +): m / z calculated C 2 iHi 6 BrN 3 0 4 S [M +] = 485.00449; found = 485.00438. IR (KBr): 1656.55, 1677.77 cnf 1 C = 0 (quinone); 1722.12 cnf 1 C = 0 (uracil). ½ NMR (CDC1 3 , 400 MHz): δ 1.36 (t, 3 J = 7.3 Hz, 3H, 6- CH2CH 3 ), 3.41 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ), 3.44 (s, 3H, 4- NCH 3 ), 3.75 (s, 3H, 2-NCH 3 ), 6.18 (s, 1H, 9-H), 7.41 (d, 3 J = 8.4 Hz, 2H, 2 'and 6 '), 7.66 (d, 3 J = 8.4 Hz, 2H, 3' and 5 ') · 13 C NMR (CDCI3, 100 MHz): δ 12.2 (6-CH 2 CH 3 ), 29.2 (4-NCH 3 ) , 30.3 (2- NCH 3 ), 31.9 (6- CH2CH3), 105.5 (10b), 120.5 (6a), 125.8 (4 '), 126.4 (1'), 128.1 (9), 133.9 (2C, 3 'and 5 '), 137.3 (2C, 2' and 6 '), 147.3 (10a), 151.2 (3), 152.9 (1), 156.0 (8), 158.5 (4a), 170.9 (6), 180.7 (7), 181.4 (10).
Ejemplo 18 Obtención de 6-etil-8- (4-hidroxitiofenil) -2 , - dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (18) . Example 18 Obtaining 6-ethyl-8- (4-hydroxythiophenyl) -2, - dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (18).
Figure imgf000077_0001
Figure imgf000077_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (311,05 mg, 0,85 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 4-hidroxitiofenol (52, 80 mg, 0,41 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0,040-0,063 mm) utilizando como fase móvil diclorometano : acetato de étilo =9:0,8. Se obtiene un sólido de color naranjo, 127,2 mg, 0,3 mmol, con 72% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone (1) (311.05 mg, 0.85 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 10 (10 ml), a solution of 4-hydroxythiophenol (52, 80) is added dropwise mg, 0.41 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: ethyl acetate = 9: 0.8. An orange solid, 127.2 mg, 0.3 mmol, is obtained in 72% yield.
Ejemplo 19 Obtención de 6-etil-2 , 4-dimetil-8- (4- nitrotiofenil) pirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) - tetraona (19) . Example 19 Obtaining 6-ethyl-2,4-dimethyl-8- (4- nitrothiophenyl) pyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (19).
Figure imgf000078_0001
Figure imgf000078_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (300, 00 mg, 1,0 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 4-ni trotiofenol (77,80 mg, 0,5 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 15:1:3. Se obtiene un sólido de color naranjo, 220,5 mg, 0,49 mmol, con 96% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (300.00 mg, 1.0 mmol), cerium (III) trichloride heptahydrate (0.5 mol% of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 ml), a solution of 4-nitrothiophenol (77, is added dropwise) 80 mg, 0.5 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane: ethyl acetate: petroleum ether = 15: 1: 3 as the mobile phase. An orange solid, 220.5 mg, 0.49 mmol, is obtained in 96% yield.
1H RMN (DMSOd6, 400 MHz) : δ 1.36 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.40 (c, 3J=7.3 Hz, 2H, 6-CH2CH3) , 3.42 (s, 3H, 4-NCH3) , 3.75 (s, 3H, 2-NCH3) , 6.24 (s, 1H, 9-H) , 7.76 (d, 2H, 2'-H y 6'-H ), 8.34 (d, 2H, 3'-H y 5'-H) . Ejemplo 20 1H NMR (DMSOd6, 400 MHz): δ 1.36 (t, 3J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.40 (c, 3J = 7.3 Hz, 2H, 6-CH 2 CH 3 ), 3.42 ( s, 3H, 4-NCH 3 ), 3.75 (s, 3H, 2-NCH 3 ), 6.24 (s, 1H, 9-H), 7.76 (d, 2H, 2'-H and 6'-H), 8.34 (d, 2H, 3'-H and 5'-H). Example 20
Obtención de 8- ( -aminotiofenil) -6-etil dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (20) . Obtaining 8- (-aminothiophenyl) -6-ethyl dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (20).
Figure imgf000079_0001
Figure imgf000079_0001
Una solución de 6-etil-2 , 4-dimetil-8- ( 4- nitrotiofenil) pirimido [4, 5-c] isoquinolin-1, 3, 7, 10 (2H, 4H) - tetraona 19 (100,00 mg, 0,33 mmol), se agregan a una solución de agua: ácido acético: metanol = 1:1:1 (30 mL) que contiene de Fe0 (368 mg, 6,6 mmol) y se agita durante 3 horas a 50°C. Transcurrido este tiempo la se agregan 100 mL de agua y se neutraliza con NaHCC>3 y luego se extrae utilizando diclorometano (30 mL x 3) .Posterior a esto la fase orgánica se seca con NaS04 anhidro, se filtra y se seca al vacio. Finalmente el crudo de reacción se purifica con 60 g de Silica gel (0,040-0,063 mm) utilizando como fase móvil diclorometano: acetato de étilo: = 9:1,5. Se obtiene un sólido de color café, 30,5 mg, 0.07 mmol, con 32,1% rendimiento. A solution of 6-ethyl-2,4-dimethyl-8- (4- nitrothiophenyl) pyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone 19 (100.00 mg , 0.33 mmol), are added to a solution of water: acetic acid: methanol = 1: 1: 1 (30 mL) containing Fe 0 (368 mg, 6.6 mmol) and stirred for 3 hours at 50 ° C After this time, 100 mL of water are added and neutralized with NaHCC> 3 and then extracted using dichloromethane (30 mL x 3). After this the organic phase is dried with anhydrous NaS0 4 , filtered and dried in vacuo . Finally, the reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: ethyl acetate: = 9: 1.5. A brown solid, 30.5 mg, 0.07 mmol, is obtained with 32.1% yield.
Ejemplo 21 Example 21
Obtención de 8- (2 , 6-dimetoxitiofenil) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H , 4H) -tetraona (21) . Obtaining 8- (2,6-dimethoxythiophenyl) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (21).
Figure imgf000080_0001
Figure imgf000080_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (106,3 mg, 0,36 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 2 , 6-dimetoxitiofenol (30,20 mg, 0,18 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0,040-0,063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo=9 : 1 : 3. Se obtiene un sólido de color rojo, 52,5 mg, 0,11 mmol, con 63% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (106.3 mg, 0.36 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 ml), a solution of 2,6-dimethoxythiophenol (30) is added dropwise , 20 mg, 0.18 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 mL) from a side key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: ethyl acetate: petroleum ether = 9: 1: 3. A red solid, 52.5 mg, 0.11 mmol, is obtained in 63% yield.
Ejemplo 22 Example 22
Obtención de 8- (5-bromo-2-metoxi eniltio) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (22) Obtaining 8- (5-bromo-2-methoxy enylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (22)
Figure imgf000081_0001
Figure imgf000081_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (109,2 mg, 0,36 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 5-bromo-2-metoxitiofenol (39,97 mg, 0,18 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0,040-0,063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 20:1:4. Se obtiene un sólido de color naranj o, 71,8 mg, 0,14 mmol, con 76% rendimiento . Ejemplo 23 A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (109.2 mg, 0.36 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 ml), a solution of 5-bromo-2-methoxythiophenol is added dropwise (39.97 mg, 0.18 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 mL) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: ethyl acetate: petroleum ether = 20: 1: 4. An orange solid, 71.8 mg, 0.14 mmol, is obtained in 76% yield. Example 23
Obtención de 8- (3 , 5-diclorotiofenil) -6-etil-2 , - dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (23) . Obtaining 8- (3, 5-dichlorothiophenyl) -6-ethyl-2, - dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (23).
Figure imgf000082_0001
Figure imgf000082_0001
23  2. 3
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (104,4 mg, 0,35 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 3 , 5-diclorotiofenol (31,6 mg, 0,18 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 20:1:7. Se obtiene un sólido de color amarillo, 58,2 mg, 0,12 mmol, con 69% rendimiento. Ejemplo 24 A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (104.4 mg, 0.35 mmol), Cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 mL), a solution of 3, 5-dichlorothiophenol (31) is added dropwise , 6 mg, 0.18 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 mL) from a side key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: ethyl acetate: petroleum ether = 20: 1: 7. A yellow solid, 58.2 mg, 0.12 mmol, is obtained in 69% yield. Example 24
Obtención de 8- (benciltio) -6-etil-2 , 4-dimetilpirimido [4 , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (24) . Obtaining 8- (benzylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (24).
Figure imgf000083_0001
Figure imgf000083_0001
24  24
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (101,2 mg, 0,34 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de bencilmercaptano (20,99 mg, 0,17 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano: acetato de étilo: éter de petróleo = 9:1:3. Se obtiene un sólido de color amarillo-anaran ado, 47,3 mg, 0,11 mmol, con 66% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tratraone (1) (101.2 mg, 0.34 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 ml), a solution of benzylmercaptan (20.99 mg, is added dropwise) 0.17 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane as mobile phase: acetate ethyl: petroleum ether = 9: 1: 3. A yellow-orange solid, 47.3 mg, 0.11 mmol, is obtained in 66% yield.
Ejemplo 25 Example 25
Obtención de 8- (4-clorobenciltio) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (25) . Obtaining 8- (4-chlorobenzylthio) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (25).
Figure imgf000084_0001
Figure imgf000084_0001
i  i
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona (1) (229, 0 mg, 0,77 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de 4-nitrotiofenol (63,30 mg, 0,40 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 10:1:5. Se obtiene un sólido de color naranjo, 111,2 mg, 0,24 mmol, con 32% rendimiento. Ejemplo 26 A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone (1) (229.0 mg, 0.77 mmol), cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 ml), a solution of 4-nitrotiophenol (63.30 is added dropwise) mg, 0.40 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 mL) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane: ethyl acetate: petroleum ether = 10: 1: 5 as mobile phase. An orange solid, 111.2 mg, 0.24 mmol, is obtained in 32% yield. Example 26
Obtención de 6-etil-2 , 4-dimetil-8- (fenetiltio) pirimido [4 , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (26) . Obtaining 6-ethyl-2, 4-dimethyl-8- (phenethylthio) pyrimido [4,5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (26).
Figure imgf000085_0001
Figure imgf000085_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona (1) (203, 4 mg, 0,68 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de feniletilmercaptano (47,0 mg, 0,34 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 10:1:6. Se obtiene un sólido de color amarillo-anaran ado, 117,2 mg, 0,27 mmol, con 79% rendimiento . Ejemplo 27 A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1,3,7,10 (2H, 4JJ) -tetraone (1) (203.4 mg, 0.68 mmol), Cerium (III) trichloride heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 mL), a solution of phenylethylmercaptan (47.0 mg, is added dropwise 0.34 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 ml) from a side key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane: ethyl acetate: petroleum ether = 10: 1: 6 as mobile phase. A yellow-orange solid, 117.2 mg, 0.27 mmol, is obtained in 79% yield. Example 27
Obtención de 8- (benzotiazol-2-iltio) -6-etil dimetilpirimido [ , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (27) . Obtaining 8- (benzothiazol-2-ylthio) -6-ethyl dimethylpyrimido [, 5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (27).
Figure imgf000086_0001
Figure imgf000086_0001
Una solución de 6-etil-2 , 4 -dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (197, 34 mg, 0,65 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (10 mi), se le adiciona mediante goteo una solución de benzotiazol (61,6 mg, 0,37 mmol) disuelto en CH2CI2 : EtOH= 1:1 (35 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 9:1:3. Se obtiene un sólido de color amarilllo, 121,2 mg, 0,26 mmol, con 71% rendimiento. Ejemplo 28 A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (197, 34 mg, 0.65 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (10 ml), a solution of benzothiazole (61.6 mg, 0, is added dropwise) 37 mmol) dissolved in CH 2 CI 2 : EtOH = 1: 1 (35 ml) from a side-key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane: ethyl acetate: petroleum ether = 9: 1: 3 as the mobile phase. A yellow solid, 121.2 mg, 0.26 mmol, is obtained in 71% yield. Example 28
Obtención del 8- (2-bromo-4-clorotiofenil) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (28) Obtaining 8- (2-bromo-4-chlorothiophenyl) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (28)
Figure imgf000087_0001
Figure imgf000087_0001
A una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraona 1 (431,2 mg, 1,96 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 :MetOH=l : 1 (10 mi), se adiciona mediante goteo una solución de 4-cloro-2-bromo-tiofenol (164,1 mg, 1,0 mmol) disuelto en CH2CI2 :MetOH=l : 1 (30 mi) desde una bureta de llave lateral a una velocidad aproximada de lml/30min por 16 horas. El crudo de reacción se purifica con 140 g de silica gel (0,040-0,063 mm) utilizando la fase móvil: acetato de étilo: diclorometano : éter de petróleo = 1:4:5. Se obtiene un sólido de color naranjo, 324,7 mg, 0,6 mmol, con 87% rendimiento. Punto Fusión 198,4 - 200,2 °C. Masa Exacta = 518, 96552. To a solution of 6-ethyl-2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4JJ) -tetraone 1 (431.2 mg, 1.96 mmol), trichloride of cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : MetOH = 1: 1 (10 ml), a solution of 4-chloro-2-bromo-thiopheneol is added dropwise (164.1 mg, 1.0 mmol) dissolved in CH 2 CI 2 : MetOH = 1: 1 (30 ml) from a side key burette at an approximate rate of lml / 30min for 16 hours. The reaction crude is purified with 140 g of silica gel (0.040-0.063 mm) using the mobile phase: ethyl acetate: dichloromethane: petroleum ether = 1: 4: 5. An orange solid, 324.7 mg, 0.6 mmol, is obtained with 87% performance. Melting Point 198.4 - 200.2 ° C. Exact Mass = 518, 96552.
½ RMN (CDC13, 400 MHz) : δ 1.38 (t, 3J=7.2 Hz, 3H, 6-CH2CH3) ; 3.42 (c, 3J=7.2 Hz, 2H, 6-CH2CH3) ; 3.45 (s, 3H, 4-NCH3) ; 3.76½ NMR (CDC1 3 , 400 MHz): δ 1.38 (t, 3 J = 7.2 Hz, 3H, 6-CH 2 CH 3 ); 3.42 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ); 3.45 (s, 3H, 4-NCH 3 ); 3.76
(s, 3H, 2-NCH3) ; 6.07 (s, 1H, 9-H) ; 7.44 (dd, 3,4J=8.3,1.9 Hz, 1H, 5') ; 7.59 (d, 3J=8.3 Hz, 1H, 6' ) ; 7.82 (d, 4J=l .9 Hz, 1H, 3') · 13C RMN (CDCI3, 100 MHz) : δ 12,10 (6-CH2CH3) ; 29, 08 (4- NCH3) ; 30, 22 (2-NCH3) ; 31,74 (6-CH2CH3) ; 105, 52 (10a) ; 120,47 (6a) ; 127,35 (9) ; 127,96 (1') ; 129,53 (5') ; 131,28 (2') ; 132,42 (4') ; 138,18 (3') ; 138,46 (6') ; 147,10 (10b) ; 151,04(s, 3H, 2-NCH 3 ); 6.07 (s, 1H, 9-H); 7.44 (dd, 3.4 J = 8.3.1.9 Hz, 1H, 5 '); 7.59 (d, 3 J = 8.3 Hz, 1H, 6 '); 7.82 (d, 4 J = 1 .9 Hz, 1H, 3 ') · 13 C NMR (CDCI3, 100 MHz): δ 12.10 (6-CH 2 CH 3 ); 29, 08 (4- NCH 3 ); 30, 22 (2-NCH3); 31.74 (6-CH 2 CH 3 ); 105, 52 (10a); 120.47 (6a); 127.35 (9); 127.96 (1 '); 129.53 (5 '); 131.28 (2 '); 132.42 (4 '); 138.18 (3 '); 138.46 (6 '); 147.10 (10b); 151.04
(3) ; 152,82 (1) ; 153,43 (8) ; 158,32 (4a) ; 170,85 (6) ; 180,50(3) ; 152.82 (1); 153.43 (8); 158.32 (4a); 170.85 (6); 180.50
(10) ; 180, 99 (7) . Ejemplo 29 (10); 180, 99 (7). Example 29
Obtención de 8- (4-amino-fenilamino) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 , 3 , 7 , 10 (2H, 4H) -tetraona (29) . Obtaining 8- (4-amino-phenylamino) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (29).
Figure imgf000088_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (100,0 mg, 0,33 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de : EtOH=l : 1 (20 mi), se le adiciona 1 , 4-fenilendiamina (72,2 mg, 0,66 mmol) y se deja reaccionar durante 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040- 0,063 mm) utilizando como fase móvil cloroformo: acetato de étilo = 8:1. Se obtiene un sólido de color verde, 69,1 mg, 0,17 mmol, con 51% rendimiento.
Figure imgf000088_0001
A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (100.0 mg, 0.33 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of: EtOH = 1: 1 (20 ml), 1,4-phenylenediamine (72.2 mg, 0.66 mmol) is added and Let react for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using as chloroform mobile phase: ethyl acetate = 8: 1. A green solid, 69.1 mg, 0.17 mmol, is obtained in 51% yield.
Ejemplo 30 Example 30
Obtención de 6-etil-2 , -dimetil-8- ( enilamino) pirimido [ , 5- c] isoquinolin-1, 3, 7, 10 (2H,4H) -tetraona (30) . Obtaining 6-ethyl-2, -dimethyl-8- (enylamino) pyrimido [, 5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone (30).
Figure imgf000089_0001
Figure imgf000089_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona 1 (100,0 mg, 0,33 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1 ) en una mezcla de CH2Cl2:EtOH=l : 1 (20 mi), se le adiciona anilina (61,5 mg, 0,66 mmol) y se deja reaccionar durante 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0.040-0.063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 1:2:4. Se obtiene un sólido de color morado, 97,6 mg, 0,25 mmol, con 76% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone 1 (100.0 mg, 0.33 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 Cl 2 : EtOH = 1: 1 (20 mL), aniline (61.5 mg, 0.66 mmol) is added and allowed to react for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane: ethyl acetate: petroleum ether = 1: 2: 4 as mobile phase. A purple solid, 97.6 mg, 0.25 mmol, is obtained in 76% yield.
Ejemplo 31 Example 31
Obtención de 6-etil-8- ( ( -fluorofenil) amino) dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (31) . Obtaining 6-ethyl-8- ((-fluorophenyl) amino) dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (31).
Figure imgf000090_0001
Figure imgf000090_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (100,0 mg, 0,33 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2Cl2:EtOH=l : 1 (20 mi), se le adiciona 4-fluor-anilina (73,3 mg, 0,66 mmol) y se deja reaccionar durante 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil cloroformo: acetato de étilo: éter de petróleo = 10:3:3. Se obtiene un sólido de color morado, 94,3 mg, 0,23 mmol, con 70% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (100.0 mg, 0.33 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 Cl 2 : EtOH = 1: 1 (20 ml), 4-fluorine-aniline (73.3 mg, 0.66 is added mmol) and allowed to react for 16 hours. The crude The reaction is purified with 60 g of Silica gel (0.040-0.063 mm) using as chloroform mobile phase: ethyl acetate: petroleum ether = 10: 3: 3. A purple solid, 94.3 mg, 0.23 mmol, is obtained in 70% yield.
Ejemplo 32 Example 32
Obtención de 8- ( (4-clorofenil) amino) -6-etil dimetilpirimido [ , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (32) . Obtaining 8- ((4-chlorophenyl) amino) -6-ethyl dimethylpyrimido [, 5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (32).
Figure imgf000091_0001
Figure imgf000091_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona 1 (100,0 mg, 0,33 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2Cl2:EtOH=l : 1 (20 mi), se le adiciona 4-cloro-anilina (84,2 mg, 0,66 mmol) y se deja reaccionar durante 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil cloroformo: acetato de étilo: éter de petróleo = 2:1:2. Se obtiene un sólido de color morado, 72,2 mg, 0,17 mmol, con 52% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone 1 (100.0 mg, 0.33 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 Cl 2 : EtOH = 1: 1 (20 ml), 4-chloro-aniline (84.2 mg, 0.66 is added mmol) and allowed to react for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using chloroform: ethyl acetate as mobile phase: petroleum ether = 2: 1: 2. A purple solid, 72.2 mg, 0.17 mmol, is obtained in 52% yield.
1H RMN (CDC13, 400 MHz) : δ 1.36 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) , 3.40 (c, 3J=7.3 Hz, 2H, 6-CH2CH3) , 3.47 (s, 3H, 4-NCH3) , 3.76 (s, 3H, 2-NCH3) , 6.40 (s, 1H, 9-H) , 7.20 (d, 3J=8.8 Hz, 2H, 2'- H y 6'-H) 7.39 (d, 3J=8.8 Hz, 2H, 3 ' -H y 5'-H) , 7.56 (1H, NH) . Ejemplo 33 1H NMR (CDC13, 400 MHz): δ 1.36 (t, 3J = 7.3 Hz, 3H, 6-CH 2 CH 3 ), 3.40 (c, 3J = 7.3 Hz, 2H, 6-CH 2 CH 3 ), 3.47 ( s, 3H, 4-NCH 3 ), 3.76 (s, 3H, 2-NCH 3 ), 6.40 (s, 1H, 9-H), 7.20 (d, 3J = 8.8 Hz, 2H, 2'- H and 6 '-H) 7.39 (d, 3J = 8.8 Hz, 2H, 3'-H and 5'-H), 7.56 (1H, NH). Example 33
Obtención de 8- ( -bromo-fenilamino) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (33) . Obtaining 8- (-bromo-phenylamino) -6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (33).
Figure imgf000092_0001
Figure imgf000092_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4JJ) -tetraona 1 (100,0 mg, 0,33 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2Cl2:EtOH=l : 1 (20 mi), se le adiciona 4-bromo-anilina (113,5 mg, 0,66 mmol) y se deja reaccionar durante 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040-0, 063 mm) utilizando como fase móvil diclorometano : acetato de étilo: éter de petróleo = 4:1:4. Se obtiene un sólido de color morado, 103,2 mg, 0,22 mmol, con 67% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone 1 (100.0 mg, 0.33 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 Cl 2 : EtOH = 1: 1 (20 mL), 4-bromo-aniline (113.5 mg, 0.66 mmol) is added and allowed to react for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using dichloromethane: ethyl acetate: petroleum ether = 4: 1: 4 as mobile phase. A purple solid, 103.2 mg, 0.22 mmol, is obtained in 67% yield.
Ejemplo 34 Example 34
Obtención de 8- (4-metilester- enilamino) -6-etil dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (34) Obtaining 8- (4-methyl-enylamino) -6-ethyl dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (34)
Figure imgf000093_0001
Figure imgf000093_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (103,0 mg, 0,33 mmol), tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en una mezcla de CH2CI2 : EtOH=l : 1 (20 mi), se le adiciona 4-metilesteranilina (97, 7 mg, 0,66 mmol) y se deja reaccionar durante 16 horas. El crudo de reacción se purifica con 60 g de Silica gel (0, 040- 0,063 mm) utilizando como fase móvil cloroformo: acetato de étilo = 20:1. Se obtiene un sólido de color rojo, 55,8 mg, 0,12 mmol, con 36% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (103.0 mg, 0.33 mmol), trichloride cerium (III) heptahydrate (0.5% mol of 1) in a mixture of CH 2 CI 2 : EtOH = 1: 1 (20 ml), 4-methylteraniline is added (97.7 mg, 0.66 mmol) and allowed to react for 16 hours. The reaction crude is purified with 60 g of Silica gel (0.040-0.063 mm) using as chloroform mobile phase: ethyl acetate = 20: 1. A red solid, 55.8 mg, 0.12 mmol, is obtained in 36% yield.
Ejemplo 35 Example 35
Obtención de 8,9-bistiofenil-6-etil-2,4-dimetil-pirimido[4,5 c] isoquinolin-1 ,3,7,10 (2H,4H) -tetraona (35) . Obtaining 8,9-bistiophenyl-6-ethyl-2,4-dimethyl-pyrimido [4,5 c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (35).
Figure imgf000094_0001
Figure imgf000094_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (102,6 mg, 1,0 mmol), tiofenol (101,8 mg, 2,8 mmol) tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en etanol (40 mi), se mantiene a reflujo durante 1 hora. Se cambia a baño maria a 70°C durante 2 horas.A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (102.6 mg, 1.0 mmol), thiophenol ( 101.8 mg, 2.8 mmol) cerium (III) trichloride heptahydrate (0.5% mol of 1) in ethanol (40 ml), is refluxed for 1 hour. It is changed to a water bath at 70 ° C for 2 hours.
Luego se mantuvo se agita a temperatura ambiente durante 18 h. El crudo de reacción se purifica con 70 g de silica gel (0,040-0,063 mm) utilizando como fase móvil: acetato de étilo : diclorometano : éter de petróleo =1,0:4,0:5,0. Se obtiene un sólido de color rojo, 68,1 mg (0,13 mmol), con 39% rendimiento. Punto Fusión 188,9 - 191,5 °C. Masa Exacta= 515, 09735. Then kept stirring at room temperature for 18 h. The reaction crude is purified with 70 g of silica gel (0.040-0.063 mm) using as mobile phase: ethyl acetate: dichloromethane: petroleum ether = 1.0: 4.0: 5.0. A red solid, 68.1 mg (0.13 mmol), is obtained with 39% yield. Melting Point 188.9-191.5 ° C. Exact Mass = 515, 09735.
½ RMN (CDCI3, 400 MHz) : δ 1,13 (t, 3J=7,3 Hz, 3H, 6-CH2CH3) ;½ NMR (CDCI3, 400 MHz): δ 1.13 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 );
3,06 (c, 3J=7,3 Hz, 2H, 6-CH2CH3) ; 3,31 (s, 3H, 4-NCH3) ; 3,71 (s, 3H, 2-NCH3) ; 7,30 (m, 3H, 8,9-SC6H5); 7,41 (m, 5H, 8,9-3.06 (c, 3 J = 7.3 Hz, 2H, 6-CH 2 CH 3 ); 3.31 (s, 3H, 4-NCH 3 ); 3.71 (s, 3H, 2-NCH3); 7.30 (m, 3H, 8.9-SC 6 H 5 ); 7.41 (m, 5H, 8.9-
SC6H5) ; 7,56 (dd, 3J=6,7 Hz, 2H, 2' ', 6' ') . 13C RMN (CDCI3, 100SC 6 H 5 ); 7.56 (dd, 3 J = 6.7 Hz, 2H, 2 ', 6''). 13 C NMR (CDCI3, 100
MHz) : δ 12,33 (6-CH2CH3); 28, 76 (4-NCH3); 30, 06 (2-NCH3); 31,01MHz): δ 12.33 (6-CH 2 CH 3 ); 28, 76 (4-NCH 3 ); 30, 06 (2-NCH 3 ); 31.01
(6-CH2CH3); 104,80 (lOb-C); 122,12 (6a-C); 127,93 (9-C);(6-CH 2 CH 3 ); 104.80 (10-C); 122.12 (6a-C); 127.93 (9-C);
128,93; 129,27; 129,42; 130,19; 131,23; 133,16; 133,30; 143,68; 147,74 (lOa-C); 150,50 (3-C); 151,09 (1-C); 152,07 (8-128.93; 129.27; 129.42; 130.19; 131.23; 133.16; 133.30; 143.68; 147.74 (10-C); 150.50 (3-C); 151.09 (1-C); 152.07 (8-
C) ; 157, 63 (4a-C); 169,91 (6-C); 176, 79 (7-C); 179, 33 (10-C) . C) ; 157, 63 (4a-C); 169.91 (6-C); 176, 79 (7-C); 179, 33 (10-C).
Ejemplo 36 Obtención de 8 , 9-bis (4-clorotiofenil) -6-etil-2 , 4- dimetilpirimido [4 , 5-c] isoquinolin-1 ,3,7,10 (2H, 4H) -tetraona (36) .
Figure imgf000096_0001
Example 36 Obtaining 8,9-bis (4-chlorothiophenyl) -6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone (36) .
Figure imgf000096_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (131,4 mg, 1,0 mmol) , 4- clorotiofenol (162,9 mg, 2,5 mmol) tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en etanol (40 mi), se mantuvo a reflujo durante 3 horas a 70°C. Luego se mantuvo en agitación a temperatura ambiente durante 18 h. El crudo de reacción se purificó con 70 g de silica gel (0, 040-0, 063 mm) utilizando como fase móvil: acetato de étilo : diclorometano : éter de petróleo =2,0:2,0:6,0. Se obtuvo un sólido de color café, 64,2 mg, 0,11 mmol, con 49% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (131.4 mg, 1.0 mmol), 4- chlorothiophenol (162.9 mg, 2.5 mmol) cerium (III) trichloride heptahydrate (0.5% mol of 1) in ethanol (40 ml), was refluxed for 3 hours at 70 ° C. Then it was kept under stirring at room temperature for 18 h. The reaction crude was purified with 70 g of silica gel (0.040-0.063 mm) using as mobile phase: ethyl acetate: dichloromethane: petroleum ether = 2.0: 2.0: 6.0. A brown solid, 64.2 mg, 0.11 mmol, was obtained in 49% yield.
Punto Fusión 207.8 - 209.8 °C. Masa Exacta=583.01940. Melting Point 207.8 - 209.8 ° C. Exact Mass = 583.01940.
½ RMN (CDC13, 400 MHz) : δ 1.17 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) ; 3.10 (c, 3J=7.3 Hz, 2H, 6-CH2CH3) ; 3.33 (s, 3H, 4-NCH3) ; 3.71 (s, 3H, 2-NCH3) ; 7.29 (d, 3J=8.8 Hz, 2H, 2' ', 6' ') ; 7.36 (d, 3J=8.7 Hz, 2H, 2', 6') ; 7.36 (d, 3J=8.7 Hz, 2H, 3', 5') ; 7.49 (d, 3J=8.7 Hz, 2H, 3' ', 5' ') . ½ NMR (CDC1 3 , 400 MHz): δ 1.17 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ); 3.10 (c, 3 J = 7.3 Hz, 2H, 6-CH 2 CH 3 ); 3.33 (s, 3H, 4-NCH 3 ); 3.71 (s, 3H, 2-NCH 3 ); 7.29 (d, 3 J = 8.8 Hz, 2H, 2 '' , 6 '' ); 7.36 (d, 3 J = 8.7 Hz, 2H, 2 ' , 6 ' ); 7.36 (d, 3 J = 8.7 Hz, 2H, 3 ' , 5 ' ); 7.49 (d, 3 J = 8.7 Hz, 2H, 3 ', 5'').
13C RMN (CDCI3, 100 MHz) : δ 12,31 (6-CH2CH3); 28, 76 (4-NCH3) ; 30, 09 (2-NCH3) ; 31,16 (6-CH2CH3) ; 104, 76 (lOb-C) ; 121,75 (6a- C) ; 128,18 (9-C) ; 129,48; 129,69; 131,43; 132,63; 134,35; 134,76; 135,72; 142,32; 147,77 (lOa-C) ; 151,01 (3-C) ; 151,24 (1-C) ; 152,14 (8-C) ; 157,61 (4a-C) ; 170,15 (6-C) ; 176,40 (7- C) ; 179, 45 (10-C) . 13 C NMR (CDCI3, 100 MHz): δ 12.31 (6-CH 2 CH 3 ); 28, 76 (4-NCH 3 ); 30, 09 (2-NCH 3 ); 31.16 (6-CH 2 CH 3 ); 104, 76 (10-C); 121.75 (6a-C); 128.18 (9-C); 129.48; 129.69; 131.43; 132.63; 134.35; 134.76; 135.72; 142.32; 147.77 (10-C); 151.01 (3-C); 151.24 (1-C); 152.14 (8-C); 157.61 (4a-C); 170.15 (6-C); 176.40 (7- C); 179, 45 (10-C).
Ejemplo 37 Example 37
Obtención de 8- (2 ' -bromo-4 ' -cloro-tiofenil ) -6-etil-7 dihidroxi-2, 4-dimetilpirimido [4, 5-c] isoquinolina-1 , 3 (2H, 4H) diona. (37) Obtaining 8- ( 2'- bromo-4 ' -chloro-thiophenyl) -6-ethyl-7 dihydroxy-2, 4-dimethylpyrimido [4,5-c] isoquinoline-1, 3 (2H, 4H) dione. (37)
Figure imgf000097_0001
Figure imgf000097_0001
37  37
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona 1 (108,1 mg, 1,0 mmol), 4-cloro-2- bromo-tiofenol (159,1 mg, 1,97 mmol) tricloruro de cerio(III) heptahidratado (0,5% mol de 1) en CH2C12 :MeOH=l : 1 (40 mL) , se lleva a 50°C durante 2 horas. Luego se mantiene en agitación a temperatura ambiente durante 18 h. El crudo de reacción se purifica con 140 g de gel de sílice (0, 040-0, 063 mm) utilizando como fase móvil : acetato de etilo : diclorometano : éter de petróleo=l : 10 : 9. Se obtiene un sólido de color amarillo, 70,3 mg (0,1 mmol) con 26% rendimiento. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone 1 (108.1 mg, 1.0 mmol), 4- Chloro-2- bromo-thiophenol (159.1 mg, 1.97 mmol) cerium (III) trichloride heptahydrate (0.5% mol of 1) in CH 2 C1 2 : MeOH = 1: 1 (40 mL), is brought to 50 ° C for 2 hours. It is then kept under stirring at room temperature for 18 h. The reaction crude is purified with 140 g of silica gel (0.040-0.063 mm) using as mobile phase: ethyl acetate: dichloromethane: petroleum ether = 1: 10: 9. A colored solid is obtained yellow, 70.3 mg (0.1 mmol) with 26% yield.
Punto Fusión 223,1 - 224,2 °C. Masa Exacta = 520,98117. Melting Point 223.1 - 224.2 ° C. Exact Mass = 520.98117.
½ RMN (CDCI3, 400 MHz) : δ 1,40 (t, 3J=7,2 Hz, 3H, 6-CH2CH3) ;½ NMR (CDCI3, 400 MHz): δ 1.40 (t, 3 J = 7.2 Hz, 3H, 6-CH 2 CH 3 );
3,61 (s, 3H, 4-NCH3) ; 3,62 (c, 3J=7,2 Hz, 2H, 6-CH2CH3) ; 3,893.61 (s, 3H, 4-NCH3); 3.62 (c, 3 J = 7.2 Hz, 2H, 6-CH 2 CH 3 ); 3.89
(s, 3H, 2-NCH3) ; 6,62 (d, 3J=8.5 Hz, 1H, 6'); 7,09 (dd, 3'4J=8,5(s, 3H, 2-NCH 3 ); 6.62 (d, 3 J = 8.5 Hz, 1H, 6 '); 7.09 (dd, 3 ' 4 J = 8.5
H<, 2,1 Hz, 1H, 5'); 7,28 (s, 1H, 9-H) ; 7,48 (s, 1H, 7-OH) ;H <, 2.1 Hz, 1H, 5 '); 7.28 (s, 1H, 9-H); 7.48 (s, 1 H, 7-OH);
7,59 (d, 3J= 2,1, 1H, 3'); 11,87 (s, 1H, 10-OH) . 13C RMN (CDCI3, 100 MHz) : δ 12,74 (6-CH2CH3); 29, 92 (4-NCH3); 30, 88 (2-7.59 (d, 3J = 2.1, 1H, 3 '); 11.87 (s, 1 H, 10-OH). 13 C NMR (CDCI 3 , 100 MHz): δ 12.74 (6-CH 2 CH 3 ); 29, 92 (4-NCH 3 ); 30, 88 (2-
NCH3) ; 34, 96 (6-CH2CH3); 98, 96 (10a); 113,01 (6a); 116,09 (9);NCH 3 ); 34, 96 (6-CH 2 CH 3 ); 98, 96 (10a); 113.01 (6a); 116.09 (9);
122,00; 127,46; 128,30; 128,33; 128,47; 132,78; 132,86 (10b);122.00; 127.46; 128.30; 128.33; 128.47; 132.78; 132.86 (10b);
138, 84 (3); 147, 65 (1); 149, 90 (8); 150, 35 (4a); 150, 52 (6);138, 84 (3); 147, 65 (1); 149, 90 (8); 150, 35 (4a); 150, 52 (6);
165, 27 (10) ; 173,35 (7) . 165, 27 (10); 173.35 (7).
Ejemplo 38 Example 38
Obtención de 8-tiopropil-6-etil-2 , 4-dimetil-pirimido [4 , 5- c]isoquinolin-l,3,7,10 (2H, 4H) -tetraona (38) .
Figure imgf000099_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1 , 3 , 7 , 10 ( 2H, 4H) -tetraona 1 (103,8 mg, 1,0 mmol), propanetiol (76,2 mg, 2,4 mmol) tricloruro de cerio(III) heptahidratado (0,5% mol de 1), se mantiene en agitación a temperatura ambiente por 16 horas. El crudo de reacción se purifica con 60 g de silica gel (0, 040-0, 063 mm) utilizando la fase móvil : acetato de étilo : diclorometano : éter de petróleo=l : 2 : 7. Se obtiene un sólido de color naranjo, 30,5 mg, 0,08 mmol, con 24% rendimiento. Punto Fusión 163,8 - 164,9 °C. Masa Exacta = 373, 10963. Obtaining 8-thiopropyl-6-ethyl-2,4-dimethyl-pyrimido [4,5- c] isoquinolin-l, 3,7,10 (2H, 4H) -tetraone (38).
Figure imgf000099_0001
A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone 1 (103.8 mg, 1.0 mmol), propanethiol ( 76.2 mg, 2.4 mmol) cerium (III) trichloride heptahydrate (0.5% mol of 1), is kept under stirring at room temperature for 16 hours. The reaction crude is purified with 60 g of silica gel (0.040-0.063 mm) using the mobile phase: ethyl acetate: dichloromethane: petroleum ether = 1: 2: 7. An orange solid is obtained , 30.5 mg, 0.08 mmol, with 24% yield. Melting Point 163.8-164.9 ° C. Exact Mass = 373, 10963.
½ RMN (CDC13, 400 MHz) : δ 1.11 (t, 3J=7,3 Hz, 3H, 8-CH2CH2CH3) ; 1.35 (t, 3J=7.3 Hz, 3H, 6- CH2CH3 ) ; 1.82 (h, 2H, 8- CH2CH2CH3 ) ; 2.81 (t, 3J=7.3 Hz, 3H, 8- CH2CH2CH3 ) ; 3.39 (c, 3J=7,3 Hz, 2H, 6- CH2CH3 ) ; 3.48 (s, 3H, 4-NCH3) ; 3.76 (s, 3H, 2-NCH3) ; 6.69 (s, 1H, 9-H) . ±JC RMN (CDCI3, 100 MHz) : δ 12,14 (6-CH2CH3); 13,66 (8-½ NMR (CDC1 3 , 400 MHz): δ 1.11 (t, 3 J = 7.3 Hz, 3H, 8-CH 2 CH 2 CH 3 ); 1.35 (t, 3 J = 7.3 Hz, 3H, 6- CH2CH 3 ); 1.82 (h, 2H, 8-CH2CH2CH 3 ); 2.81 (t, 3 J = 7.3 Hz, 3H, 8- CH2CH2CH 3 ); 3.39 (c, 3 J = 7.3 Hz, 2H, 6- CH2CH 3 ); 3.48 (s, 3H, 4-NCH 3 ); 3.76 (s, 3H, 2-NCH 3 ); 6.69 (s, 1H, 9-H). ± J C NMR (CDCI 3 , 100 MHz): δ 12.14 (6-CH 2 CH 3 ); 13.66 (8-
CH2CH2CH3) ; 20.89 (8-CH2CH2CH3) ; 29.08 (4-NCH3); 30,17 (2-NCH3);CH2CH2CH3); 20.89 (8-CH2CH2CH3); 29.08 (4-NCH 3 ); 30.17 (2-NCH 3 );
31,72 (6-CH2CH3) ; 32, 76 ( 8 -CH2CH2CH3 ) ; 105, 42 (10a); 120,8431.72 (6-CH 2 CH 3 ); 32, 76 (8 -CH 2 CH 2 CH 3 ); 105, 42 (10a); 120.84
(6a); 126,46 (9); 147,15 (10b); 151,14 (3); 152,69 (1); 155,40 (8); 158,55 (4a); 170,74 (6); 180,79 (10); 180,79 (7) . (6a); 126.46 (9); 147.15 (10b); 151.14 (3); 152.69 (1); 155.40 (8); 158.55 (4a); 170.74 (6); 180.79 (10); 180.79 (7).
Ejemplo 39 Example 39
Obtención de 8 , 9-bis-tiopropil-6-etil-2 , -dimetil pirimido [4 , 5-c] isoquinolin-1 , 3 , 7 , 10 (2Η, 4Η) -tetraona (39) . Obtaining 8,9-bis-thiopropyl-6-ethyl-2, -dimethyl pyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2Η, 4Η) -tetraone (39).
Figure imgf000100_0001
Figure imgf000100_0001
Una solución de 6-etil-2 , 4-dimetilpirimido [ 4 , 5-c] isoquinolin- 1 , 3 , 7 , 10 ( 2H, 4JJ) -tetraona 1 (120,5 mg, 1,0 mmol), propanetiol (73,5 mg, 2,4 mmol) tricloruro de cerio(III) heptahidratado (0,5% mol de 1), 72 mg trietilamina (68% mol de propanetiol) disuelto en EtOH : CH2Cl2=l : 1 (40 mi), se mantiene a reflujo por 4 horas. El crudo de reacción se purifica con 70 g de silica gel (0,040-0,063 mm) utilizando la fase móvil: acetato de étilo: diclorometano : éter de petróleo =0,5:2,5:7. Se obtuvo un sólido de color rojo, 155,5 mg, 0,35 mmol, con 86% rendimiento. Punto Fusión 138,9 - 140,2 °C. Masa Exacta = 447, 12865. A solution of 6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin-1, 3, 7, 10 (2H, 4JJ) -tetraone 1 (120.5 mg, 1.0 mmol), propanethiol ( 73.5 mg, 2.4 mmol) cerium (III) trichloride heptahydrate (0.5% mol of 1), 72 mg triethylamine (68% mol of propanethiol) dissolved in EtOH: CH 2 Cl 2 = 1: 1 ( 40 mi), is refluxed for 4 hours. The reaction crude is purified with 70 g of silica gel (0.040-0.063 mm) using the mobile phase: ethyl acetate: dichloromethane: petroleum ether = 0.5: 2.5: 7. A Red solid, 155.5 mg, 0.35 mmol, with 86% yield. Melting Point 138.9 - 140.2 ° C. Exact Mass = 447, 12865.
½ RMN (CDC13, 400 MHz) : δ 1.11 (t, 3J=7,3 Hz, 3H, 8-CH2CH2CH3) ; 1.35 (t, 3J=7.3 Hz, 3H, 6-CH2CH3) ; 1.82 (h, 2H, 8-CH2CH2CH3) ; 2.81 (t, 3J=7.3 Hz, 3H, 8-CH2CH2CH3) ; 3.39 (c, 3J=7.3 Hz, 2H, 6- CH2CH3) ; 3.48 (s, 3H, 4-NCH3) ; 3.76 (s, 3H, 2-NCH3) ; 6.69 (s, 1H, 9-H) . 13C RMN (CDC13, 100 MHz) : δ 12.14 (6-CH2CH3); 13.66 (8-CH2CH2CH3) ; 20.89 ( 8-CH2CH2CH3) ; 29.08 (4-NCH3); 30.17 (2- NCH3) ; 31.72 (6-CH2CH3); 32.76 ( 8-CH2CH2CH3) ; 105.42 (10a); 120.84 (6a); 126.46 (9); 147.15 (10b); 151.14 (3); 152.69 (1); 155.40 (8); 158.55 (4a); 170.74 (6); 180.79 (10); 180.79 (7) . ½ NMR (CDC1 3 , 400 MHz): δ 1.11 (t, 3 J = 7.3 Hz, 3H, 8-CH 2 CH 2 CH 3 ); 1.35 (t, 3 J = 7.3 Hz, 3H, 6-CH 2 CH 3 ); 1.82 (h, 2H, 8-CH 2 CH 2 CH 3 ); 2.81 (t, 3 J = 7.3 Hz, 3H, 8-CH 2 CH 2 CH 3 ); 3.39 (c, 3 J = 7.3 Hz, 2H, 6- CH 2 CH 3 ); 3.48 (s, 3H, 4-NCH 3 ); 3.76 (s, 3H, 2-NCH 3 ); 6.69 (s, 1H, 9-H). 13 C NMR (CDC1 3 , 100 MHz): δ 12.14 (6-CH 2 CH 3 ); 13.66 (8-CH 2 CH 2 CH 3 ); 20.89 (8-CH 2 CH 2 CH 3 ); 29.08 (4-NCH 3 ); 30.17 (2- NCH 3 ); 31.72 (6-CH 2 CH 3 ); 32.76 (8-CH 2 CH 2 CH 3 ); 105.42 (10a); 120.84 (6a); 126.46 (9); 147.15 (10b); 151.14 (3); 152.69 (1); 155.40 (8); 158.55 (4th); 170.74 (6); 180.79 (10); 180.79 (7).
Donde el compuesto descrito en el ejemplo 1, es un compuesto intermediario, asi mismo la síntesis de compuestos intermediarios G que comprende las etapas de: a) hacer reaccionar los siguientes compuestos: Where the compound described in example 1 is an intermediate compound, likewise the synthesis of intermediate compounds G comprising the steps of: a) reacting the following compounds:
Figure imgf000102_0001
Figure imgf000102_0001
Cojupaesfe íntermediaris G Cojupaesfe intermediaris G
I donde R3 es -H, alquilo C1-C15, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R6 es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: - CO-Z-alquilo C1-C15, -Z-CO-alquilo C1-C15, -H, -ter-butilo, - iso-propilo, -alquilo C1-C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, - 0-R7,-CN, -S-R7, -S-CF3 y fenilo sustituido a su vez con -H, - alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R es un grupo -H, alquilo C1-C15, -OH; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo ; donde heteroarilo se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono; para obtener el compuesto intermediaro G. I where R 3 is -H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2, -OR 6 , -SR 6 ; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 6 is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl, phenyl, heterocycle and heteroaryl are: - CO-Z-C1-C15 alkyl, -Z-CO-C1-C15 alkyl, -H, -ter-butyl, - iso-propyl, -C1-C15 alkyl, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 and phenyl substituted in turn with -H, - C1-C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 ; where R is a group -H, C1-C15 alkyl, -OH; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; where heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, having 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms; to obtain the intermediate compound G.
Los compuestos obtenidos en los Ejemplos 1 hasta 39 están representados por la siguiente fórmula estructural, como se muestra en la Tabla I que sigue: Tabla The compounds obtained in Examples 1 to 39 are represented by the following structural formula, as shown in Table I below: Table
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000107_0001
Figure imgf000108_0001
Descripción de figuras: Figura 1/3 Description of figures: Figure 1/3
Esta figura representa la cadena transportadora de electrones (CTe) .  This figure represents the electron transport chain (CTe).
A. Es una representación del flujo normal de electrones a través de los complejos de la CTe, en donde la energía desprendida de este flujo de electrones se utiliza para la translocación de protones en contra de gradiente, el cual es un proceso energéticamente desfavorable. El gradiente electroquímico generado es utilizado para la formación de ATP mediante un proceso favorable energéticamente. A. It is a representation of the normal flow of electrons through the CTe complexes, where the energy released from this flow of electrons is used for the translocation of protons against the gradient, which is an energetically unfavorable process. The electrochemical gradient generated is used for the formation of ATP through an energy-efficient process.
B. Representación del bloqueo en el flujo de electrones que efectuán los compuestos quinónicos de la presente invención (Q) al emular a la ubiquinona. Esto conlleva a un descenso en la generación de ATP y/o a la producción de ROS. B. Representation of the blockage in the flow of electrons effected by the quinonic compounds of the present invention (Q) when emulating the ubiquinone. This leads to a decrease in the generation of ATP and / or the production of ROS.
Figura 2/3 Figure 2/3
Esta figura presenta un gráfico donde se muestra el aumento de las tasas de resistencia de tres bacterias que son motivo de preocupación para las autoridades de salud pública: (MRSA) , (VRE) y (FQRP). This figure presents a graph showing the increase in resistance rates of three bacteria that are cause for concern for public health authorities: (MRSA), (VRE) and (FQRP).
Estos datos se obtuvieron de las unidades de cuidados intensivos de los hospitales que participan en el sistema Nacional de Vigilancia de Infecciones Nosocomiales de EE.UU. These data were obtained from the intensive care units of the hospitals that participate in the US National Nosocomial Infection Surveillance system.
MRSA: Staphylococcus aureus resistente a meticilina MRSA: Methicillin-resistant Staphylococcus aureus
VRE: Enterococos resistentes a vancomicina VRE: Vancomycin Resistant Enterococci
FQRP: Pseudomonas aeruginosa resistente a las fluoroquinolonas Figura 3/3  FQRP: Pseudomonas aeruginosa resistant to fluoroquinolones Figure 3/3
Esta figura presenta un diagrama superior donde se verificó la actividad del compuesto del ejemplo 16 de formula I contra bacterias Gram (-) del tipo Echerichia Coli ATCC©25922.  This figure shows a diagram above where the activity of the compound of example 16 of formula I against Gram (-) bacteria of the Echerichia Coli ATCC © 25922 type was verified.
El diagrama inferior muestra la actividad del compuesto del ejemplo 16 de formula I contra bacterias Gram (-) del tipo Pseudomona Aeruginosa ATCC©27853. The diagram below shows the activity of the compound of example 16 of formula I against Gram (-) bacteria of the Pseudomona Aeruginosa ATCC © 27853 type.
Para eso se combino el compuesto de formula I (Ejemplo 16) con diferentes concentraciones de EDTA. Pruebas experimentales For that, the compound of formula I (Example 16) was combined with different concentrations of EDTA. Experimental tests
Estos compuestos son sometidos a ensayo con respecto a su actividad in vitro (Screening Actividad antibacteriana CIM ( g/mL) ) y los resultados se indican en la Tabla II. These compounds are tested for their in vitro activity (Screening CIM antibacterial activity (g / mL)) and the results are indicated in Table II.
Tabla II Table II
Screening Actividad antibacteriana CIM (p.g/m )  Screening CIM antibacterial activity (p.g / m)
Staphylococcus Staphylococcus Staphylococcus Staphylococcus
aureus aureus Enterococcus Eschericha Pseudomona aureus aureus Enterococcus Eschericha Pseudomona
Molécula Molecule
meticilino meticilino faecalis coli aeruginosa resistente sensible  meticillin meticillin faecalis coli aeruginosa sensitive sensitive
ATCC 43300 ATCC 29213 ATCC 29212 ATCC 25922 ATCC 27853 ATCC 43300 ATCC 29213 ATCC 29212 ATCC 25922 ATCC 27853
1 >32 >32 >32 >32 >32 1> 32> 32> 32> 32> 32
2 8 8 8 >32 >32 2 8 8 8> 32> 32
3 32 32 >32 >32 >32 3 32 32> 32> 32> 32
4 2 4 4 >32 >32 4 2 4 4> 32> 32
5 >32 >32 >32 >32 >32 5> 32> 32> 32> 32> 32
6 >32 >32 >32 >32 >32 6> 32> 32> 32> 32> 32
7 1 4 2 >32 >32 4 4 4 >32 >327 1 4 2>32> 32 4 4 4>32> 32
4 8 4 >32 >324 8 4> 32> 32
4 4 8 >32 >324 4 8> 32> 32
2 32 4 >32 >322 32 4> 32> 32
2 32 4 >32 >322 32 4> 32> 32
4 4 16 >32 >324 4 16> 32> 32
16 16 16 >32 >3216 16 16> 32> 32
8 8 8 >32 >328 8 8> 32> 32
4 4 4 >32 >324 4 4> 32> 32
4 8 8 >32 >32 4 8 8> 32> 32
Luego del Screening Actividad antibacteriana se realizaron pruebas para verificar la actividad antibacteriana en una población heterogénea de bacterias, donde los resultados pueden verse en la siguiente tabla III. After Screening Antibacterial activity tests were performed to verify antibacterial activity in a heterogeneous population of bacteria, where the results can be seen in the following table III.
Tabla III Table III
Origen n° de Rango CIM50 CIM90 MG CIM  Origin No. of Range CIM50 CIM90 MG CIM
Aislamientos CIM  CIM insulations
Aspirado 10 4-2 2 4 2,40 traqueal  Aspirated 10 4-2 2 4 2.40 tracheal
Herida 10 4-2 2 2 2,20 Wound 10 4-2 2 2 2.20
Sangre 11 32-1 2 4 4,81Blood 11 32-1 2 4 4.81
Otros 2 4-2 2 4 3,00Other 2 4-2 2 4 3.00
TOTAL 33 4-1 2 2 3,10TOTAL 33 4-1 2 2 3.10
Origen n° de Rango CIM50 CIM90 MG CIM Origin No. of Range CIM50 CIM90 MG CIM
Aislamientos CIM  CIM insulations
Aspirado 9 4-1 2 4 2,33 traqueal  Aspirated 9 4-1 2 4 2.33 tracheal
Herida 9 4-1 2 4 2, 11 Wound 9 4-1 2 4 2, 11
Sangre 9 2-1 2 2 1,77Blood 9 2-1 2 2 1.77
Otros 2 4-2 2 4 3,00Other 2 4-2 2 4 3.00
TOTAL 29 4-1 2 4 2,30TOTAL 29 4-1 2 4 2.30
Origen n° de Rango CIM50 CIM90 MG CIM Origin No. of Range CIM50 CIM90 MG CIM
Aislamientos CIM  CIM insulations
Orina 10 4-2 2 4 2, 67 Urine 10 4-2 2 4 2, 67
Liquido 10 4-2 2 2 2,20 peritoneal Herida 10 4--2 2 4 2,80Liquid 10 4-2 2 2 2.20 peritoneal Wound 10 4--2 2 4 2.80
Sangre 10 4- -2 2 4 2, 60Blood 10 4- -2 2 4 2, 60
Otros 4 4- -2 2 4 2,50Other 4 4- -2 2 4 2.50
TOTAL 44 4- -2 2 4 2,59 TOTAL 44 4- -2 2 4 2.59
Bacterias utilizadas: Para el screening de actividad antibacteriana de los compuestos compuestos se utilizó un panel de cepas prototipo: Bacteria used: For the screening of antibacterial activity of the compound compounds a panel of prototype strains was used:
♦ Staphylococcus aureus resistente a meticilina ATCC© 43300. ♦ Methicillin resistant Staphylococcus aureus ATCC © 43300.
♦ Staphylococcus aureus sensible a meticilina ATCC© 29213.♦ Methicillin-sensitive Staphylococcus aureus ATCC © 29213.
♦ Enterococcus faecalis ATCC© 29212. ♦ Enterococcus faecalis ATCC © 29212.
♦ Eschericha coli ATCC© 25922.  ♦ Eschericha coli ATCC © 25922.
♦ Pseudomona aeruginosa ATCC© 27853.  ♦ Pseudomona aeruginosa ATCC © 27853.
Los compuestos que resultaron más activos se ensayaron sobre un panel de 89 aislamientos clínicos de cocacceas Gram positivas aislados de distintos centros hospitalarios chilenos de durante el año 2014. Los aislamientos utilizados fueron Staphylococcus aureus resistente a meticilina y Enterococcus spp . Resistente a vancomicina que cumplieran con un perfil de susceptibilidad de multi-resistencia definido por aquellos aislamientos que presentaran resistencia a lo menos un representante de 2 o más familias de antibacterianos. Los sitios de origen de asilamiento fueron aspirado traqueal, herida y sangre para Staphylococcus aureus , en tanto a los sitios para Enterococcus spp fueron orina, liquido peritoneal, sangre y herida. The compounds that were most active were tested on a panel of 89 clinical isolates of Gram-positive cocacceae isolated from different Chilean hospitals during 2014. The isolates used were methicillin-resistant Staphylococcus aureus and Enterococcus spp. Vancomycin resistant that met a multi-resistance susceptibility profile defined by those isolates that presented resistance to at least one representative of 2 or more families of antibacterials. The sites of origin of isolation were aspirated tracheal, wound and blood for Staphylococcus aureus, while the sites for Enterococcus spp were urine, peritoneal fluid, blood and wound.
Las cepas fueron sembradas desde el cepario (donde se conservaban en glicerol 50% v/v y caldo de cultivo Brain Heart Infusión, a -20°C) en agar Mueller-Hinton (Oxoid, Inglaterra) . The strains were sown from the cepary (where 50% v / v glycerol and Brain Heart Infusion culture broth, at -20 ° C) were stored in Mueller-Hinton agar (Oxoid, England).
Para la determinación de la concentración inhibitoria mínima (CIM) , se usó la técnica de microdilución en caldo de cultivo de acuerdo al protocolo sugerido por la CLSI, brevemente: En placas de cultivo de 96 pocilios estériles (8 filas y 12 columnas) (Ultracruz™ Polystyrene Microplates, 96 well, U bottom Santa Cruz biotechnology, inc.) se agregaron 100 uL de caldo Müeller Hinton en todos los pocilios, para luego agregar 100 uL de antibiótico control o compuesto a ensayar en las 8 filas de la primera columna, para continuar haciendo diluciones seriadas con un factor de dilución de 0,5. Las concentraciones a ensayar van desde 32 hasta 0,0625 g/mL. Los pocilios de las columnas 11 y 12 se utilizaron para control positivo de crecimiento y control de esterilidad respectivamente . For the determination of the minimum inhibitory concentration (MIC), the microdilution technique in culture broth was used according to the protocol suggested by the CLSI, briefly: In sterile 96-well culture plates (8 rows and 12 columns) (Ultracruz ™ Polystyrene Microplates, 96 well, U bottom Santa Cruz biotechnology, inc.) 100 uL of Müeller Hinton broth was added in all wells, then added 100 uL of control or compound antibiotic to be tested in the 8 rows of the first column, to continue making serial dilutions with a dilution factor of 0.5. The concentrations to be tested range from 32 to 0.0625 g / mL. The wells of columns 11 and 12 were used for control Positive growth and sterility control respectively.
Una vez preparada la placa, se agregaron 100 uL de la suspensión bacteriana a evaluar ajustada previamente al 0,5 Me Farland, en cada uno de los pocilios excluyendo a los pocilios de la columna 12. Finalmente, las placas fueron tapadas y llevadas a incubar a 36°C por 18 a 24 horas, transcurrido el tiempo, las placas fueron observadas utilizando luz de contraste a fin de determinar la concentración a la cual se inhibe el crecimiento bacteriano (indicada por la desaparición de turbidez ) . Once the plate was prepared, 100 uL of the bacterial suspension to be evaluated was previously adjusted to 0.5 Me Farland, in each of the wells excluding the wells in column 12. Finally, the plates were covered and incubated. at 36 ° C for 18 to 24 hours, after the time elapsed, the plates were observed using contrast light in order to determine the concentration at which bacterial growth is inhibited (indicated by the disappearance of turbidity).
Todos, los ensayos fueron realizados por triplicado, y se consideraron como válidos aquellos resultados en los cuales los controles internos de cada placa (control de crecimiento y de esterilidad) fueran adecuados, asi como también se evaluó la CIM de antibióticos control ( ciprofloxacino, gentamicina y vancomicina) y se contrasto con los rangos permitidos de control de calidad dados por la CLSI, si la CIM detectada en el ensaya estaba dentro de los rangos el ensayo se aceptaba como válido . Los compuestos de esta invención son útiles para el tratamiento de enfermedades infecciosas, de preferencia multiresistentes a antibióticos en mamíferos, por ejemplo, humanos . All trials were performed in triplicate, and those results in which the internal controls of each plate (growth control and sterility) were adequate were considered valid, as well as the MIC of control antibiotics (ciprofloxacin, gentamicin) and vancomycin) and contrasted with the permitted quality control ranges given by the CLSI, if the MIC detected in the test was within the ranges the test was accepted as valid. The compounds of this invention are useful for the treatment of infectious diseases, preferably multiresistant to antibiotics in mammals, for example, humans.
La descripción anterior detalla los métodos y composiciones específicos que pueden emplearse para llevar a la práctica la presente invención y representa el mejor modo contemplado. Sin embargo, resulta evidente para un experto en el arte que otros compuestos con las propiedades farmacológicas deseadas pueden prepararse en una forma análoga, y que los compuestos revelados pueden también obtenerse a partir de diferentes compuestos de partida vía diferentes reacciones químicas. En forma similar, pueden prepararse y utilizarse composiciones farmacéuticas diferentes con sustancialmente los mismos resultados. De este modo, sin embargo, y aunque lo anterior puede aparecer detallado en el texto, no debería interpretarse como limitativo del alcance general de la presente. Por el contrario, el ámbito de la presente invención está regida solamente por la interpretación legal de las reivindicaciones adjuntas. Por otro lado se realizaron pruebas para verificar la actividad contra bacterias Gram (_), se probaron 2 cepas, Echerichia Coli ATCC©25922 y Pseudomona Aeruginosa ATCC©27853. Para eso se combino el compuesto de formula I (Ejemplo 16) con diferentes concentraciones de EDTA entregando los siguientes resultados presentados en la figura 3/3. The above description details the specific methods and compositions that can be used to carry out the present invention and represents the best mode contemplated. However, it is apparent to one skilled in the art that other compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions can be prepared and used with substantially the same results. Thus, however, and although the above may appear detailed in the text, it should not be construed as limiting the general scope of the present. On the contrary, the scope of the present invention is governed only by the legal interpretation of the appended claims. On the other hand, tests were carried out to verify the activity against Gram bacteria ( _ ), 2 strains were tested, Echerichia Coli ATCC © 25922 and Pseudomona Aeruginosa ATCC © 27853. To that end, the compound of formula I (Example 16) was combined with different concentrations of EDTA giving the following results presented in Figure 3/3.
En resumen, los resultados obtenidos nos señalan que el EDTA permite al antibiótico de formula I actuar sobre las cepas Gram (-) en un rango de concentración entre 10 a 800 g/ml de preferencia en el rango de 64 a 128 g/ml . In summary, the results obtained indicate that EDTA allows the antibiotic of formula I to act on Gram (-) strains in a concentration range between 10 to 800 g / ml, preferably in the range of 64 to 128 g / ml.
Por otro lado y de manera general, el estado del arte utilizado en ele presente desarrollo se resume en el siguiente listado : On the other hand and in a general way, the state of the art used in the present development is summarized in the following list:
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Claims

RE IVINDICACIONES RE IVINDICATIONS
1.- Compuestos derivados pirimido-isoquinolin-quinonicos CARACTERIZADOS porque comprenden compuestos de formula I o sus tautómeros o sales farmacéuticamente aceptables 1.- Pyrimido-isoquinolin-quinonicos derivative compounds CHARACTERIZED because they comprise compounds of formula I or their pharmaceutically acceptable tautomers or salts
R5 R 5
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000128_0001
alquilo C1-C15, -Si-R , -SiO-R , -NH- ( CH2 ) n-R , -N ( ( CH2 ) n-R ) 2' -0- (CH2)n-R6, -S- (CH2)n-R6' -Si- (CH2)n-R6; donde R es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: -CO-Z-alquilo C1-C15, -Z-CO- alquilo C1-C15, -H, -ter-butilo, -iso-propilo, -alquilo Ci- C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S- CF3 y fenilo sustituido a su vez con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde X es O, N o S; donde n= 0-14; donde m= 0-14; donde 0= 1-14; donde K, Z, P, G, I, Y, J y W son independientemente: O, N, S02, SO, S, C o Si;
Figure imgf000128_0001
C1-C15 alkyl, -Si-R, -SiO-R, -NH- (CH 2 ) n -R, -N ((CH 2 ) n -R) 2 '-0- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 '-Si- (CH 2 ) n -R 6 ; where R is a C 1 -C 15 alkyl group, a substituted C 1 -C 15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C 1 - alkyl groups C15, aryl, phenyl, heterocycle and heteroaryl are: -CO-Z-C 1 -C15 alkyl, -Z-CO-C 1 -C15 alkyl, -H, -ter-butyl, -iso-propyl, -Ci-alkyl C15, -CF 3 , halogen of the group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2, -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 and substituted phenyl in turn with -H, -C1-C15 alkyl, halogen of the group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH; where X is O, N or S; where n = 0-14; where m = 0-14; where 0 = 1-14; where K, Z, P, G, I, Y, J and W are independently: O, N, S0 2 , SO, S, C or Si;
R2 es -H, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6 y halógeno del grupo de Cl, Br, F y I; R 2 is -H, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 and halogen of the group Cl, Br, F and I ;
R3 es H, alquilo C1-C15, -NH2 , -OH, -SH, -NH-R6, -N-(R6)2,-0- R6,-S-R6; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, 0, y S, en el anillo; donde heteroarilo se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, 0, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: - H, -alquilo C1-C15, alquilo sustituido C1-C15 con R7, R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -0- R 6 , -SR 6 ; where heterocycle is defined as a monocyclic ring, containing approximately 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, 0, and S, in the ring; where heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, having between 1 to 4 heteroatoms selected from N, 0, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: - H, -C1-C15 alkyl, substituted C1-C15 alkyl with R 7 ,
halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7,- N(R7)2, -C00H, -C00-R7, -0C0-R7, -0-R7,-CN, -S-R7, -S-CF3, - ter-butilo, -iso-propilo y -CF3. halogen of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 , - tert-butyl, -iso-propyl and -CF 3 .
2.- Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS porque 2. Pyrimido-isoquinolin-quinone derivatives, according to claim 1, CHARACTERIZED because
R1 es -NH- (CH2) n-R6, -0- ( CH2 ) n-R6, -S- (CH2) n-R6; donde R6 es un grupo fenilo sustituido, donde las sustituciones del grupo fenilo son independientemente: -Z- CO-alquilo C1-C15, -CO-Z-alquilo C1-C15, -H, -ter-butilo, iso-propilo, -alquilo C1-C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7 , -N (R7 ) 2 , -COOH, -COO-R7, - OCO-R7, -0-R7,-CN, -S-R7, -S-CF3y fenilo sustituido con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -NO2, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S- R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde n= 0-2; donde z es independientemente: O, N, S02, SO, S, C o Si; R2 es H; R 1 is -NH- (CH 2 ) n -R 6 , -0- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 ; where R 6 is a substituted phenyl group, where the substitutions of the phenyl group are independently: -Z- CO-C 1 -C15 alkyl, -CO-Z-C 1 -C15 alkyl, -H, -ter-butyl, iso-propyl, -C 1 -C15 alkyl, -CF 3 , halo of the group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , - OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 and phenyl substituted with -H, -C 1 -C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -NO 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -S- R 7 , -S-CF 3 ; where R 7 is a group -H, C 1 -C 15 alkyl, -OH; where n = 0-2; where z is independently: O, N, S0 2 , SO, S, C or Si; R 2 is H;
R3 es H y alquilo C1-C15, donde R4 y R5 son H, un grupo alquilo C1-C15. R 3 is H and C 1 -C 15 alkyl, where R 4 and R 5 are H, a C 1 -C 15 alkyl group.
3.- Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS porque 3. Pyrimido-isoquinolin-quinonic derivatives, according to claim 1, CHARACTERIZED because
R1 es -NH- (CH2) n-R6, -O- ( CH2 ) n-R6, -S- (CH2) n-R6; donde R es un grupo alquilo C1-C15 o un grupo fenilo sustituido, donde las sustituciones del grupo fenilo son independientemente: -H, -alquilo C1-C15 y halógeno del grupo de Cl, Br, F y I; donde n= 0-2; R 1 is -NH- (CH 2 ) n -R 6 , -O- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 ; where R is a C 1 -C 15 alkyl group or a substituted phenyl group, where the substitutions of the phenyl group are independently: -H, -C 1 -C 15 alkyl and halogen of the group of Cl, Br, F and I; where n = 0-2;
R2 es -H, -NH-R6, -N- (R6) 2, -O-R6, -S-R6; R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15; R 2 is -H, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 ; R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group;
4.- Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 3, CARACTERIZADOS porque las sustituciones R6 del grupo fenilo están en posiciones orto y para. 4. Pyrimido-isoquinolin-quinonic derivative compounds according to claim 3, CHARACTERIZED because the R 6 substitutions of the phenyl group are in ortho and para positions.
5. - Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS donde: 5. - Pyrimido-isoquinolin-quinonic derivative compounds according to claim 1, CHARACTERIZED wherein:
Figure imgf000132_0001
donde X es O, N o S R es -H;
Figure imgf000132_0001
where X is O, N or S R is -H;
R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15. R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group.
6.- Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS donde 6. Pyrimido-isoquinolin-quinonic derivatives, according to claim 1, CHARACTERIZED wherein
Figure imgf000133_0001
donde n= 0-8; donde w es independientemente: O, N, SO2, SO, S, C o Si; donde y, z y j son C o N;
Figure imgf000133_0001
where n = 0-8; where w is independently: O, N, SO 2 , SO, S, C or Si; where y, z and j are C or N;
R es -H; R is -H;
R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: - H, -alquilo C1-C15, alquilo sustituido C1-C15 con R7, R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C 1 -C 15 alkyl group; where R 8, R 9, R 10 and R 11 are independently: -H, - C1-C15, alkyl substituted C 1-C15 with R 7,
halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, - ter-butilo, -iso-propilo y -CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH. halogen of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 , - tert-butyl, -iso-propyl and -CF 3 ; where R 7 is a group -H, C 1 -C 15 alkyl, -OH.
7.- Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS donde 7. Pyrimido-isoquinolin-quinonic derivatives, according to claim 1, CHARACTERIZED wherein
Figure imgf000134_0001
donde n= 0-8; donde m= 0-6; donde 0= 1-6; donde Z, J son independientemente: O, N, SO2, SO, S, C o Si; donde Y es C o N;
Figure imgf000134_0001
where n = 0-8; where m = 0-6; where 0 = 1-6; where Z, J are independently: O, N, SO 2 , SO, S, C or Si; where Y is C or N;
R es -H; R is -H;
R3 es H, alquilo C1-C15; R 3 is H, C1-C15 alkyl;
donde R4 y R5 son H, un grupo alquilo C1-C15; where R 4 and R 5 are H, a C1-C15 alkyl group;
8.- Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS donde
Figure imgf000135_0001
donde n= 0-8; donde z es independientemente: O, N, S02, SO, S, C o Si; donde Y es C o N; 8. Pyrimido-isoquinolin-quinonic derivatives, according to claim 1, CHARACTERIZED wherein
Figure imgf000135_0001
where n = 0-8; where z is independently: O, N, S0 2 , SO, S, C or Si; where Y is C or N;
R es -H; R is -H;
R3 es H, alquilo C1-C15; R 3 is H, C1-C15 alkyl;
donde R4 y R5 son H, un grupo alquilo C1-C15. where R 4 and R 5 are H, a C1-C15 alkyl group.
9. -Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS donde: 9. -Pyrimido-isoquinolin-quinonic derivative compounds according to claim 1, CHARACTERIZED wherein:
R1 son R 1 are
Figure imgf000136_0001
donde n= 0-8; donde k, z son independientemente: O, N, SO2, SO, S, C o Si; donde g, i, y, j y w son independientemente: N o C; R2 es -H;
Figure imgf000136_0001
where n = 0-8; where k, z are independently: O, N, SO 2 , SO, S, C or Si; where g, i, and, j and w are independently: N or C; R 2 is -H;
R3 es H, alquilo C1-C15; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R9, R10 y R11 corresponden independientemente a: -H, - alquilo C1-C15, alquilo sustituido C1-C15 con R7, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, - COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, -ter- butilo, -iso-propilo y -CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH. R 3 is H, C 1 -C 15 alkyl; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 9 , R 10 and R 11 independently correspond to: -H, - C1-C15 alkyl, C1-C15 substituted alkyl with R 7 , halo of the group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , - COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S-CF 3 , - tert-butyl, -iso-propyl and -CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH.
10. -Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1, CARACTERIZADOS porque comprenden los siguientes compuestos: 10. -Pyrimido-isoquinolin-quinonic derivative compounds according to claim 1, CHARACTERIZED because they comprise the following compounds:
6-etil-2, 4-dimetilpirimido [4, 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraona 6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraone
6-etil-2, 4-dimetil-8- ( feniltio ) pirimido [4, 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraona 6-ethyl-2, 4-dimethyl-8- (phenylthio) pyrimido [4,5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraone
6-etil-2, 4-dimetil-8- (o-toliltio) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-2, 4-dimethyl-8- (o-tolylthio) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( (2-metoxifenil) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 6-etil-8- ( (2-fluorofenil) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((2-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone 6-ethyl-8- ((2-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( (2-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((2-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 2-bromofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((2-bromophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-2, 4-dimetil-8- (m-toliltio) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-2, 4-dimethyl-8- (m-tolylthio) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( ( 3-metoxifenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((3-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( ( 3-fluorofenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((3-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 3-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((3-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 3-bromofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-etil-2, 4-dimetil-8- (p-toliltio) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((3-bromophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone 6-ethyl-2, 4-dimethyl-8- (p-tolylthio) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( ( 4-metoxifenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((4-methoxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( ( 4-fluorofenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((4-fluorophenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 4-clorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((4-chlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 4-bromofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((4-bromophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( ( 4-hidroxifenil ) tio) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((4-hydroxyphenyl) thio) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-2, 4-dimetil-8- ( (4-nitrofenil)tio) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-2, 4-dimethyl-8- ((4-nitrophenyl) thio) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 4-aminofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((4-aminophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( (2, 6-dimetoxifenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ( ( 5-bromo-2-metoxifenil ) tio) -6-etil-2, 4- dimetilpirimido [4, 5-c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((2,6-dimethoxyphenyl) thio) -6-ethyl-2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone 8- ((5-Bromo-2-methoxyphenyl) thio) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( (3, 5-diclorofenil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((3, 5-dichlorophenyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- (benciltio) -6-etil-2, 4-dimetilpirimido [4, 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraona 8- (benzylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraone
8- ( ( 4-clorobencil ) tio) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((4-Chlorobenzyl) thio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-2, 4-dimetil-8- ( fenetiltio ) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-ethyl-2, 4-dimethyl-8- (phenethylthio) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- (benzotiazol-2-iltio ) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- (benzothiazol-2-ylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 2-bromo-4-clorofenil ) tio) -6-etil-2, 4- dimetilpirimido [4, 5-c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((2-Bromo-4-chlorophenyl) thio) -6-ethyl-2, 4- dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 4-aminofenil ) amino) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 6-etil-2, 4-dimetil-8- ( fenilamino ) pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8- ((4-aminophenyl) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone 6-ethyl-2, 4-dimethyl-8- (phenylamino) pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
6-etil-8- ( ( 4-fluorofenil ) amino) -2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 6-ethyl-8- ((4-fluorophenyl) amino) -2,4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( ( 4-clorofenil ) amino) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 8- ((4-chlorophenyl) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( (4-bromofenil) amino) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona metil 4- ( (6-etil-2, 4-dimetil-l, 3,7, 10-tetraoxo- 1,2,3,4,7, 1 O-hexahidropirimido [4, 5-c] isoquinolin-8- il ) amino ) benzoato 8- ((4-bromophenyl) amino) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone methyl 4- ((6- ethyl-2, 4-dimethyl-l, 3,7, 10-tetraoxo-1,2,3,4,7, 1 O-hexahydropyrimido [4,5-c] isoquinolin-8-yl) amino) benzoate
8, 9-bis-tiofenil- 6-etil-2 , 4-dimetil-pirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 8,9-bis-thiophenyl-6-ethyl-2, 4-dimethyl-pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8, 9-bis ( 4-clorotiofenil ) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 8,9-bis (4-chlorothiophenyl) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8- ( 2 ' -bromo-4 ' -cíoro-tiofenil) -6-etil-7, 10-dihidroxi-2 , 4- dimetilpirimido [4, 5-c] isoquinolina-1 , 3 (2H, 4H) -diona 8-tiopropil- 6-etil-2 , 4-dimetil-pirimido [4, 5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraona 8- ( 2' -Bromo-4 ' -chloro-thiophenyl) -6-ethyl-7, 10-dihydroxy-2, 4- dimethylpyrimido [4,5-c] isoquinoline-1, 3 (2H, 4H) -dione 8-thiopropyl-6-ethyl-2, 4-dimethyl-pyrimido [4,5-c] isoquinolin- 1, 3, 7, 10 (2H, 4H) -tetraone
8, 9-bis-tiopropil- 6-etil-2 , 4-dimetil-pirimido [4,5- c] isoquinolin-1 , 3,7,10 (2H, 4H) -tetraona 8,9-bis-thiopropyl-6-ethyl-2, 4-dimethyl-pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
11. - Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 3, CARACTERIZADOS porque comprenden los siguientes compuestos: 11. - Pyrimido-isoquinolin-quinone derivative compounds according to claim 3, CHARACTERIZED in that they comprise the following compounds:
8, 9-bis ( 4-clorotiofenil ) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 8,9-bis (4-chlorothiophenyl) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
8, 9-bis-tiopropil- 6-etil-2 , 4-dimetil-pirimido [4,5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraona. 8,9-bis-thiopropyl-6-ethyl-2, 4-dimethyl-pyrimido [4,5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone.
8, 9-bis-tiofenil- 6-etil-2 , 4-dimetil-pirimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraona 8,9-bis-thiophenyl-6-ethyl-2, 4-dimethyl-pyrimido [4,5- c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone
12. - Compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 5, CARACTERIZADOS porque comprenden el siguiente compuesto: 12. - Pyrimido-isoquinolin-quinonic derivative compounds according to claim 5, CHARACTERIZED in that they comprise the following compound:
8- (benzotiazol-2-iltio ) -6-etil-2, 4-dimetilpirimido [4,5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraona. 8- (benzothiazol-2-ylthio) -6-ethyl-2, 4-dimethylpyrimido [4,5- c] isoquinolin-1, 3, 7, 10 (2H, 4H) -tetraone.
13.- Composición farmacéutica, según la reivindicación CARACTERIZADA porque comprende compuestos de formula I sus tautómeros o sales farmacéuticamente aceptables 13. Pharmaceutical composition according to claim CHARACTERIZED in that it comprises compounds of formula I, their tautomers or pharmaceutically acceptable salts
Figure imgf000143_0001
Figure imgf000143_0001
donde : where :
R es -H, -NH2, -OH, -SH, -NH-R , -N-(Rb)2, -0-Rb, R is -H, -NH 2 , -OH, -SH, -NH-R, -N- (R b ) 2 , -0-R b ,
R11 R10 R11 R 10
Figure imgf000143_0002
Figure imgf000144_0001
Figure imgf000143_0002
Figure imgf000144_0001
alquilo C1-C15, -Si-Rb, -SiO-Rb, -NH- (CH2) n-Rb, -N ( ( CH2 ) n-Rb) 2' -0- (CH2)n-R6, -S- (CH2)n-R6' -Si- (CH2)n-R6; donde R6 es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: -CO-Z-alquilo C1-C15, - Z - CO- alquilo C1-C15, -H, -ter-butilo, -iso-propilo, -alquilo Ci- C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7, -N (R7) 2, -C00H, -C00-R7, -0C0-R7, -0-R7,-CN, -S-R7, -S- CF3 y fenilo sustituido a su vez con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7,- N(R7)2, -C00H, -C00-R7, -0C0-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde X es O, N o S; donde n= 0-14; donde m= 0-14; donde o= 1-14; donde K, Z, P, G, I, Y, J y W son independientemente: O, N, S02, SO, S, C o Si; C1-C15 alkyl, -Si-R b , -SiO-R b , -NH- (CH 2 ) n -R b , -N ((CH 2 ) n -R b ) 2 '-0- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 '-Si- (CH 2 ) n -R 6 ; where R 6 is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl, phenyl, heterocycle and heteroaryl are: -CO-Z-C1-C15 alkyl, - Z-CO-C1-C15 alkyl, -H, -ter-butyl, -iso-propyl, -C-C15 alkyl, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 and phenyl substituted in turn with -H, -C1-C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH; where X is O, N or S; where n = 0-14; where m = 0-14; where o = 1-14; where K, Z, P, G, I, Y, J and W are independently: O, N, S0 2 , SO, S, C or Si;
R2 es -H, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6 y halógeno del grupo de Cl, Br, F y I; R 2 is -H, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 and halogen of the group Cl, Br, F and I ;
R3 es H, alquilo C1-C15, -NH2 , -OH, -SH, -NH-R6, -N-(R6)2,-0- R6,-S-R6; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo; donde heteroarilo se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: - H, -alquilo C1-C15, alquilo sustituido C1-C15 con R7, R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -0- R 6 , -SR 6 ; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; where heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 atoms in the ring, which has between 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: - H, -C1-C15 alkyl, substituted C1-C15 alkyl with R 7 ,
halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, - ter-butilo, -iso-propilo y -CF3; y excipientes farmacéuticamente aceptables. halogen of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 , - tert-butyl, -iso-propyl and -CF 3 ; and pharmaceutically acceptable excipients.
14.- Composición farmacéutica, CARACTERIZADA porque comprende compuestos de formula I o sus tautómeros o sales farmacéuticamente aceptables 14.- Pharmaceutical composition, CHARACTERIZED because it comprises compounds of formula I or their pharmaceutically acceptable tautomers or salts
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000147_0001
Figure imgf000148_0001
alquilo C1-C15, -Si-Rb, -SiO-Rb, -NH- (CH2) n-Rb, -N ( ( CH2 ) n-Rb) 2' -0- (CH2)n-R6, -S- (CH2)n-R6' -Si- (CH2)n-R6; donde R6 es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: -CO-Z-alquilo C1-C15, - Z - CO- alquilo C1-C15, -H, -ter-butilo, -iso-propilo, -alquilo Ci- C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7, -N (R7) 2, -C00H, -C00-R7, -0C0-R7, -0-R7,-CN, -S-R7, -S- CF3 y fenilo sustituido a su vez con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7,- N(R7)2, -C00H, -C00-R7, -0C0-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde X es O, N o S; donde n= 0-14; donde m= 0-14; donde o= 1-14; donde K, Z, P, G, I, Y, J y W son independientemente: O, N, S02, SO, S, C o Si; C1-C15 alkyl, -Si-R b , -SiO-R b , -NH- (CH 2 ) n -R b , -N ((CH 2 ) n -R b ) 2 '-0- (CH 2 ) n -R 6 , -S- (CH 2 ) n -R 6 '-Si- (CH 2 ) n -R 6 ; where R 6 is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl, phenyl, heterocycle and heteroaryl are: -CO-Z-C1-C15 alkyl, - Z-CO-C1-C15 alkyl, -H, -ter-butyl, -iso-propyl, -C-C15 alkyl, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 and phenyl substituted in turn with -H, -C1-C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -C00H, -C00-R 7 , -0C0-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH; where X is O, N or S; where n = 0-14; where m = 0-14; where o = 1-14; where K, Z, P, G, I, Y, J and W are independently: O, N, S0 2 , SO, S, C or Si;
R2 es -H, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6 y halógeno del grupo de Cl, Br, F y I; R 2 is -H, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -OR 6 , -SR 6 and halogen of the group Cl, Br, F and I ;
R3 es H, alquilo C1-C15, -NH2 , -OH, -SH, -NH-R6, -N-(R6)2,-0- R6,-S-R6; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo; donde heteroarilo se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R8, R9, R10 y R11 corresponden independientemente a: - H, -alquilo C1-C15, alquilo sustituido C1-C15 con R7, R 3 is H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2 , -0- R 6 , -SR 6 ; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; where heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 atoms in the ring, which has between 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 8 , R 9 , R 10 and R 11 independently correspond to: - H, -C1-C15 alkyl, substituted C1-C15 alkyl with R 7 ,
halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, - ter-butilo, -iso-propilo y -CF3; ácido etilendiaminotetraácetico ; y exipientes farmacéuticamente aceptables. halogen of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 , - tert-butyl, -iso-propyl and -CF 3 ; Ethylenediaminetetraacetic acid ; and pharmaceutically acceptable excipients.
15.- Procedimiento de preparación de los compuestos intermediarios derivados pirimido-isoquinolin-quinonicos , CARACTERIZADO porque comprende las etapas de: a) hacer reaccionar los siguientes compuestos:
Figure imgf000151_0001
15.- Procedure for preparing the intermediate compounds derived from pyrimido-isoquinolin-quinonicos, CHARACTERIZED because it comprises the steps of: a) reacting the following compounds:
Figure imgf000151_0001
donde R3 es -H, alquilo C1-C15, -NH2, -OH, -SH, -NH-R6, -N- (R6) 2, -O-R6, -S-R6; donde R4 y R5 son H, un grupo alquilo C1-C15; donde R6 es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: -CO-Z-alquilo C1-C15, -Z-CO- alquilo C1-C15, -H, -ter-butilo, -iso-propilo, -alquilo Ci- C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S- CF3 y fenilo sustituido a su vez con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R es un grupo -H, alquilo C1-C15, -OH; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo; donde heteroarilo se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono; where R 3 is -H, C1-C15 alkyl, -NH 2 , -OH, -SH, -NH-R 6 , -N- (R 6 ) 2, -OR 6 , -SR 6 ; where R 4 and R 5 are H, a C1-C15 alkyl group; where R 6 is a C1-C15 alkyl group, a substituted C1-C15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C1-C15 alkyl groups, aryl, phenyl, heterocycle and heteroaryl are: -CO-Z-C1-C15 alkyl, -Z-CO-C1-C15 alkyl, -H, -ter-butyl, -iso-propyl, -C-C15 alkyl, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2, -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 and phenyl substituted in turn with -H, -C1-C15 alkyl, halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 ; where R is a group -H, C1-C15 alkyl, -OH; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; where heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, having 1 to 4 heteroatoms selected from N, O, and S; where aryl means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms;
para obtener el compuesto intermediaro G. to obtain the intermediate compound G.
16.- Procedimiento de preparación de los compuestos 16.- Procedure of preparation of the compounds
intermediarios derivados pirimido-isoquinolin-quinonicos , según la reivindicación 15 CARACTERIZADO porque comprende las etapas de: pyrimido-isoquinolin-quinone derivatives, according to claim 15 CHARACTERIZED in that it comprises the steps of:
Figure imgf000153_0001
Figure imgf000153_0001
a) hacer reaccionar una solución de 1- (2, 5-dihidroxifenil ) - propan-l-ona con 6-amino-l , 3-dimetilpirimidina-2 , 4 ( 1H, 3H) - diona en presencia de MgS04 y Ag2Ü en un medio de CH2CI2 a temperatura ambiente. b) el sólido resultante se purifica con Silica gel utilizando como fase móvil diclorometano : acetato de étilo = 9:1, obteniendosé el compuesto intermediario 1. a) react a solution of 1- (2, 5-dihydroxyphenyl) -propan-l-one with 6-amino-l, 3-dimethylpyrimidine-2, 4 (1H, 3H) -dione in the presence of MgSO 4 and Ag 2 Ü in a medium of CH 2 CI 2 at room temperature. b) the resulting solid is purified with Silica gel using dichloromethane as mobile phase: ethyl acetate = 9: 1, obtaining intermediate compound 1.
17.- Procedimiento de preparación de los compuestos derivados pirimido-isoquinolin-quinonicos , según la reivindicación 1 CARACTERIZADO porque comprende las etapas de : c) hacer reaccionar en un medio de etanol y aire, el compuesto intermediario G 17.- Preparation process of the pyrimido-isoquinolin-quinone derivative compounds according to claim 1 CHARACTERIZED because it comprises the steps of: c) reacting in an ethanol and air medium, the intermediate compound G
Figure imgf000154_0001
Figure imgf000154_0001
donde R4 y R5 son H, un grupo alquilo C1-C15; where R 4 and R 5 are H, a C 1 -C 15 alkyl group;
con uno de los compuestos presentados a continuación:with one of the compounds presented below:
NH2-R , NH-(R )2, HO-R , NH 2 -R, NH- (R) 2 , HO-R,
Figure imgf000155_0001
Figure imgf000155_0001
HS-R , Cl-SO-R , CI-SO2-R , alquilo C1-C15, HSi-R , H-SiO-R , NH2- (CH2) n-R6, NH ( (CH2) n-R6) 2, HO- ( CH2 ) n-R6, HS- ( CH2 ) n-R6' HSi- (CH2)n-R6; donde X es O, N o S; donde n= 0-14; donde m= 0-14; donde o= 1-14; donde K, Ζ, Ρ, G, I, Y, J y W son independientemente: O, N, S02, SO, S, C o Si; donde R8, R9, R10 y R11 corresponden independientemente a: - H, -alquilo C1-C15, alquilo sustituido C1-C15 con R7, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3, - ter-butilo, -iso-propilo y -CF3; donde R6 es un grupo alquilo C1-C15, un grupo alquilo C1-C15 sustituido, fenilo, fenilo sustituido, arilo, arilo sustituido, heterociclo, heterociclo sustituido, heteroarilo, heteroarilo sustituido, donde las sustituciones de los grupos alquilo C1-C15, arilo, fenilo, heterociclo y heteroarilo son: -CO-Z-alquilo C1-C15, -Z-CO- alquilo C1-C15, -H, -ter-butilo, -iso-propilo, -alquilo Ci- C15, -CF3, halógeno del grupo de Cl, Br, F y I, -NH2 , -N02, -NH-R7, -N (R7) 2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S- CF3 y fenilo sustituido a su vez con -H, -alquilo C1-C15, halógeno del grupo de Cl, Br, F y I, -NH2, -N02, -NH-R7,- N(R7)2, -COOH, -COO-R7, -OCO-R7, -0-R7,-CN, -S-R7, -S-CF3; donde R7 es un grupo -H, alquilo C1-C15, -OH; donde heterociclo se define como un anillo monociclico, que contienen de aproximadamente entre 3 a 7 átomos en el anillo, con 1 a 5 heteroátomos seleccionados entre N, O, y S, en el anillo; donde heteroarilo se desfine como un sistema de anillo cíclico o policíclico aromático de 3 a 7 átomos en el anillo, que tiene entre 1 a 4 heteroátomos seleccionados entre N, O, y S; donde arilo significa un anillo aromático cíclico o policíclico que tiene de 5 a 12 átomos de carbono, para obtener compuestos derivados pirimido-isoquinolin- quinonicos de formula I : HS-R, Cl-SO-R, CI-SO2-R, C1-C15 alkyl, HSi-R, H-SiO-R, NH 2 - (CH 2 ) n -R 6 , NH ((CH 2 ) n -R 6 ) 2, HO- (CH 2 ) n -R 6 , HS- (CH 2 ) n -R 6 'HSi- (CH 2 ) n -R 6 ; where X is O, N or S; where n = 0-14; where m = 0-14; where o = 1-14; where K, Ζ, Ρ, G, I, Y, J and W are independently: O, N, S0 2 , SO, S, C or Si; where R 8, R 9, R 10 and R 11 are independently: -H, - C1-C15, substituted C 1-C15 with R 7, halogen group Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S -CF 3 , - tert-butyl, -iso-propyl and -CF 3 ; where R 6 is a C 1 -C 15 alkyl group, a substituted C 1 -C 15 alkyl group, phenyl, substituted phenyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, where substitutions of C 1 alkyl groups -C15, aryl, phenyl, heterocycle and heteroaryl are: -CO-Z-C 1 -C15 alkyl, -Z-CO-C 1 -C15 alkyl, -H, -ter-butyl, -iso-propyl, -Ci alkyl - C15, -CF 3 , halogen from the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , -N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , -0-R 7 , -CN, -SR 7 , -S- CF 3 and phenyl substituted with -H, -C 1 -C15 alkyl, halogen of the group of Cl, Br, F and I, -NH 2 , -N0 2 , -NH-R 7 , - N (R 7 ) 2 , -COOH, -COO-R 7 , -OCO-R 7 , - 0-R 7 , -CN, -SR 7 , -S-CF 3 ; where R 7 is a group -H, C1-C15 alkyl, -OH; where heterocycle is defined as a monocyclic ring, containing from about 3 to 7 atoms in the ring, with 1 to 5 heteroatoms selected from N, O, and S, in the ring; where heteroaryl is defined as an aromatic cyclic or polycyclic ring system of 3 to 7 ring atoms, having 1 to 4 heteroatoms selected from N, O, and S; wherein aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, to obtain pyrimido-isoquinolinquinone derivative compounds of formula I:
Figure imgf000158_0001
Figure imgf000158_0001
18.- Procedimiento de preparación de los compuestos farmacéuticos, según la reivindicación 17 CARACTERIZADO porque opcionalmente para el caso de los derivados nitrados de formula 19 se considera una etapa posterior de reducción donde :  18. Method of preparing the pharmaceutical compounds according to claim 17 CHARACTERIZED because optionally for the case of nitrated derivatives of formula 19 a subsequent reduction stage is considered where:
Figure imgf000158_0002
a) Se Hace reaccionar en una solución equimolar de agua, ácido acético y metanol el compuesto 6-etil-2 , 4-dimetil-8- ( (4-nitrofenil)tio) pirimido [4, 5-c] isoquinolin- 1 , 3 , 7 , 10 ( 2H, 4H) -tetraona 19, con hierro metálico y con NaHCC>3, para extraer utilizando diclorometano; b) Purificar en columna de Silica gel utilizando como fase móvil diclorometano: acetato de étilo: = 9:1,5 para obtener el compuesto de formula 20, 8- ( ( 4-aminofenil ) tio ) - 6-etil- 2, 4-dimetilpirimido [4, 5-c] isoquinolin-1 , 3,7,10 (2H, 4H) - tetraona .
Figure imgf000158_0002
a) The compound 6-ethyl-2,4-dimethyl-8- ((4-nitrophenyl) thio) pyrimido [4,5-c] isoquinolin- is reacted in an equimolar solution of water, acetic acid and methanol. 1, 3, 7, 10 (2H, 4H) -tetraone 19, with metallic iron and with NaHCC> 3, to extract using dichloromethane; b) Purify Silica gel column using dichloromethane: ethyl acetate: = 9: 1.5 to obtain the compound of formula 20.8- ((4-aminophenyl) thio) -6-ethyl-2, 4 -dimethylpyrimido [4,5-c] isoquinolin-1, 3,7,10 (2H, 4H) -tetraone.
19. - Uso de los compuestos derivados pirimido-isoquinolin- quinonicos, según la reivindicación 1, CARACTERIZADO porque sirven para la preparación de un medicamento útil en el tratamiento de infecciones bacterianas. 19. - Use of the pyrimido-isoquinolinquinone derivative compounds according to claim 1, CHARACTERIZED because they serve for the preparation of a medicament useful in the treatment of bacterial infections.
20. - Uso de los compuestos derivados pirimido-isoquinolin- quinonicos, según la reivindicación 19, CARACTERIZADO porque sirven para la preparación de un medicamento útil en el tratamiento de infecciones bacterianas multiresistentes a los antibióticos, tales como Staphylococcus aureus resistente a la meticilina (MRSA o SARM) , Staphylococcus aureus con resistencia intermedia a la vancomicina (VISA) , Staphylococcus aureus con resistencia a la vancomicina (VRSA) , Enterococcus resistente a la Vancomicina (VRE) , cepas EF, Staphylococcus aureus emergentes con resistencia a linezolid y/o cepas bacterianas no susceptibles a daptomicina . 20. - Use of the pyrimido-isoquinolinquinone derivative compounds according to claim 19, CHARACTERIZED because they serve for the preparation of a medicament useful in the treatment of multiresistant bacterial infections to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA or MRSA), Staphylococcus aureus with intermediate vancomycin resistance (VISA), Staphylococcus aureus with vancomycin resistance (VRSA), Vancomycin resistant Enterococcus (VRE), EF strains, emerging Staphylococcus aureus with linezolid resistance and / or strains Bacterial not susceptible to daptomycin.
21. - Uso de las composiciones farmacéuticas, según la reivindicación 14, CARACTERIZADO porque sirven para la preparación de un medicamento útil en el tratamiento de infecciones bacterianas, donde las cepas a tratar son Gram (-) · 21. - Use of the pharmaceutical compositions according to claim 14, CHARACTERIZED because they serve for the preparation of a medicament useful in the treatment of bacterial infections, where the strains to be treated are Gram (-) ·
22. - Uso de las composiciones farmacéuticas, según la reivindicación 21, CARACTERIZADO donde algunas cepas gram (-) a tratar son Echerichia Coli y Pseudomona Aeruginosa. 22. - Use of the pharmaceutical compositions according to claim 21, CHARACTERIZED wherein some gram (-) strains to be treated are Echerichia Coli and Pseudomona Aeruginosa.
23. - Compuesto intermediario según la reivindicación 15, CARACTERIZADO porque posee la estructura 23. - Intermediate compound according to claim 15, CHARACTERIZED because it has the structure
6-etil-2, 4-dimetilpirimido [4, 5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraona.  6-ethyl-2,4-dimethylpyrimido [4,5-c] isoquinolin- 1,3,7,10 (2H, 4JJ) -tetraone.
PCT/CL2016/050080 2015-12-30 2016-12-29 Pyrimido-isoquinolin-quinone derivative compounds, and pharmaceutically acceptable salts, isomers and tautomers thereof; pharmaceutical composition; preparation method; and use thereof in the treatment of diseases caused by bacteria and multidrug-resistant bacteria WO2017113031A1 (en)

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